Pyrimidine-substituted pyrrolidine derivatives, pharmaceutical compositions and uses thereof

ABSTRACT

The invention relates to new pyrrolidine derivatives of the formula 
     
       
         
         
             
             
         
       
     
     wherein R 1  to R 3 , Ar, L T and n are as defined in the description and claims, to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.

FIELD OF THE INVENTION

This invention relates to new compounds, in particularpyrimidine-substituted pyrrolidine derivatives, to processes forpreparing such compounds, to their use as inhibitors of acetyl-CoAcarboxylase(s), to methods for their therapeutic use, in particular indiseases and conditions mediated by the inhibition of acetyl-CoAcarboxylase(s), and to pharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

Obesity is a major public health issue not only for the EU, USA, Japanbut also for the world in general. It is associated with a number ofserious diseases including diabetes, dyslipidemia, hypertension,cardiovascular and cerebrovascular diseases. Although the underlyingmechanisms are not yet fully understood, the impairement of insulinaction in target tissues by accumulation of excess lipids is generallyregarded as a key mechanism linking obesity to secondary pathologies (G.Wolf, Nutrition Reviews Vol. 66(10):597-600; D B Savage, K F Petersen, GI Shulman, Physiol Rev. 2007; 87:507-520). Therefore, understanding ofcellular lipid metabolism in insulin target tissues is crucial in orderto elucidate the development of diseases associated with obesity.

A central event in lipid metabolism is the generation of malonyl-CoA viacarboxylation of acetyl-CoA by the two mammalian ACC isoforms ACC1(ACC-alpha, also termed ACCA) and ACC2 (ACC-beta, also designated ACCB)(Saggerson D. Annu Rev Nutr. 2008; 28:253-72). The malonyl-CoA generatedis used for de novo fatty acid synthesis and acts as inhibitor of CPT-1,thereby regulating mitochondrial fatty acid oxidation. Furthermore,malonyl-CoA is also described to act centrally to control food intake,and may play an important role in controlling insulin secretion from thepancreas (G D Lopaschuk, J R Ussher, J S Jaswal. Pharmacol Rev. 2010;62(2):237-64; D Saggerson Annu Rev Nutr. 2008; 28:253-72), furthercoordinating the regulation of intermediary metabolism.

Therefore ACC1 and ACC2 have been shown to be major regulators of fattyacid metabolism and are presently considered as an attractive target toregulate the human diseases of obesity, diabetes and cardiovascularcomplications (S J Wakil and L A Abu-Elheiga, J. Lipid Res. 2009. 50:S138-S143; L. Tong, H J Harwood Jr. Journal of Cellular Biochemistry99:1476-1488, 2006).

As a result of its unique position in intermediary metabolism,inhibition of ACC offers the ability to inhibit de novo fatty acidproduction in lipogenic tissues (liver and adipose) while at the sametime stimulating fatty acid oxidation in oxidative tissues (liver,heart, and skeletal muscle) and therefore offers an attractive modalityfor favorably affecting, in a concerted manner, a multitude ofcardiovascular risk factors associated with obesity, diabetes, insulinresistance, nonalcoholic steatohepatitis (NASH) and the metabolicsyndrome (L. Tong, H J Harwood Jr. Journal of Cellular Biochemistry99:1476-1488, 2006; Corbett J W, Harwood J H Jr., Recent Pat CardiovascDrug Discov. 2007 November; 2(3):162-80).

Furthermore recent data show that cellular toxicity mediated by lipids(lipotoxicity) is implicated in the susceptibitlity to diabetesassociated nephropathy (for review see M Murea, B I Freedmann, J SParks, P A Antinozzi, S C Elbein, L M Ma; Clin J Am Soc Nephrol. 2010;5:2373-9). A large-scale genome-wide association study in japanesepatients identified single nucleotide polymorphism in the ACC2 gene(ACACB) associated with diabetic nephropathy risk which was replicatedin nine independent cohorts. In the kidney, dysregulation of fatty acidmetabolism leading to increased fatty acid levels is believed to lead toglomerular and tubular dysfunction (M Murea, B I Freedmann, J S Parks, PA Antinozzi, S C Elbein, L M Ma; Clin J Am Soc Nephrol. 2010; 5:2373-9).Therefore inhibitors targeting ACC as key molecule involved in lipidoxidation have the potential to be beneficial for favorably affectingdiabetic nephropathy.

Additionally, insulin resistance, deregulated lipid metabolism,lipotoxicity and increased intramuscular lipids have also been describedto play a role in type 1 diabetes (I E Schauer, J K Snell-Bergeon, B CBergman, D M Maahs, A Kretowski, R H Eckel, M Rewers Diabetes 2011;60:306-14; P Ebeling, B Essén-Gustaysson, J A Tuominen and V A KoivistoDiabetologia 41: 111-115; K J Nadeau, J G Regensteiner, T A Bauer, M SBrown, J L Dorosz, A Hull, P Zeitler, B Draznin, J E B. Reusch J ClinEndocrinol Metab, 2010, 95:513-521). Therefore ACC inhibitors are alsoconsidered as interesting drugs for the treatment of type 1 diabetes.

In addition ACC inhibitors also have the potential to intervene in theprogression of diseases that result from the rapid growth of malignantcells or invading organisms that are dependent on endogenous lipidsynthesis to sustain their rapid proliferation. De novo lipogenesis isknown to be required for growth of many tumor cells and ACCup-regulation has been recognized in multiple human cancers, promotinglipogenesis to meet the need of cancer cells for rapid growth andproliferation (C Wang, S Rajput, K Watabe, D F Liao, D Cao Front Biosci2010; 2:515-26). This is further demonstrated in studies using ACCinhibitors which induced growth arrest and selective cytotoxicity incancer cells and by RNA interference-mediated knock-down of ACC whichinhibited growth and induced apoptosis in different types of cancercells. Furthermore, ACC1 associates with and is regulated by the breastcancer susceptibility gene 1 (BRCA1). Commonly occurring BRCA1 mutationslead to ACC1 activation and breast cancer susceptibility (C Wang, SRajput, K Watabe, D F Liao, D Cao Front Biosci 2010; 2:515-26).

Furthermore in central nervous system disorders including but notlimited to Alzheimer's disease, Parkinson disease and epilepsy,impairements in neuronal energy metabolism have been described (Ogawa M,Fukuyama H, Ouchi Y, Yamauchi H, Kimura J, J Neurol Sci. 1996;139(1):78-82). Interventions targeting this metabolic defect may provebeneficial to the patients. One promising intervention is therefore toprovide the glucose-compromised neuronscerebral brain neurons withketone bodies as an alternative substrate (ST HendersonNeurotherapeutics, 2008, 5:470-480; L C Costantini, L J Barr, J L Vogel,S T Henderson BMC Neurosci. 2008, 9 Suppl 2:S16; KW Barañano, A LHartman. Curr Treat Options Neurol. 2008; 10:410-9). ACC inhibitionleading to increased fatty acid oxidation may thereby result inincreases in the blood levels of ketone bodies thereby providing analternative energy substrate for the brain.

Preclinical and clinical evidence indicates that ketone bodies canprovide neuroprotective effects in models of Parkinson's disease, AD,hypoxia, ischemia, amyotrophic lateral sclerosis and glioma (L CCostantini, L J Barr, J L Vogel, S T Henderson BMC Neurosci. 2008, 9Suppl 2:S16) and improved cognitive scores in Alzheimers Diseasespatients (M A Reger, S T Henderson, C Hale, B Cholerton, L D Baker, G SWatson, K Hydea, D Chapmana, S Craft Neurobiology of Aging 25 (2004)311-314). The end result of increased ketone levels is an improvement inmitochondrial efficiency and reduction in the generation of reactiveoxygen species (for reviews see L C Costantini, L J Barr, J L Vogel, S THenderson BMC Neurosci. 2008, 9 Suppl 2:S16; K W Baranano, A L Hartman.Curr Treat Options Neurol. 2008; 10:410-9).

Furthermore, the potential of ACC inhibitors as antifungal agents and asantibacterial agents is well documented (L. Tong, H J Harwood Jr.Journal of Cellular Biochemistry 99:1476-1488, 2006). In addition, ACCinhibitors can be used to combat viral infections. It was discoveredrecently that viruses rely on the metabolic network of their cellularhosts to provide energy and building blocks for viral replication(Munger J, B D Bennett, A Parikh, X J Feng, J McArdle, H A Rabitz, TShenk, J D Rabinowitz. Nat. Biotechnol. 2008; 26:1179-86). A fluxmeasurement approach to quantify changes in metabolic activity inducedby human cytomegalovirus (HCMV) elucidated that infection with HCMVmarkedly changed fluxes through much of the central carbon metabolism,including glycolysis, tricarboxylic acid cycle and fatty acidbiosynthesis. Pharmacological inhibition of fatty acid biosynthesissuppressed the replication of two divergent enveloped viruses (HCMV andinfluenza A) indicating that fatty acid synthesis is essential for thereplication. These examples show that acetyl-CoA fluxes and de novofatty acid biosynthesis are critical to viral survival and propagationas the newly synthesized fatty acids and phospholipids are important forformation of viral envelopes. Changing the metabolic flux influences theabsolute quantity of phospholipid available, the chemical compositionand physical properties of the envelope negatively affect viral growthand replication. Hence, ACC inhibitors acting on key enzymes in thefatty acid metabolism, have the potential to be antiviral drugs.

Aim of the Present Invention

The aim of the present invention is to provide new compounds, inparticular new pyrrolidine derivatives, which are active with regard toacetyl-CoA carboxylase(s).

Another aim of the present invention is to provide new compounds, inparticular new pyrrolidine derivatives, which are active with regard toACC2.

A further aim of the present invention is to provide new compounds, inparticular new pyrrolidine derivatives, which have an inhibitory effecton acetyl-CoA carboxylase(s) in vitro and/or in vivo and possesssuitable pharmacological and pharmacokinetic properties to use them asmedicaments.

A further aim of the present invention is to provide new compounds, inparticular new pyrrolidine derivatives, which have an inhibitory effecton ACC2 in vitro and/or in vivo and possess suitable pharmacological andpharmacokinetic properties to use them as medicaments.

A further aim of the present invention is to provide effective ACCinhibitors, in particular for the treatment of metabolic disorders, forexample of obesity and/or diabetes.

A further aim of the present invention is to provide methods fortreating a disease or condition mediated by the inhibition of acetyl-CoAcarboxylase(s) in a patient.

A further aim of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further aim of the present invention is to provide a combination of atleast one compound according to the invention with one or moreadditional therapeutic agents.

A further aim of the present invention is to provide methods for thesynthesis of the new compounds, in particular pyrrolidine derivatives.

A further aim of the present invention is to provide starting and/orintermediate compounds suitable in methods for the synthesis of the newcompounds.

Further aims of the present invention become apparent to the one skilledin the art by the description hereinbefore and in the following and bythe examples.

OBJECT OF THE INVENTION

Within the scope of the present invention it has now surprisingly beenfound that the new compounds of general formula (I) as describedhereinafter exhibit an inhibiting activity with regard to acetyl-CoAcarboxylase(s).

According to another aspect of the present invention it has been foundthat the new compounds of general formula (I) as described hereinafterexhibit an inhibiting activity with regard to ACC2.

In a first aspect the present invention provides a compound of generalformula

wherein

-   Ar is selected from the group Ar-G1 consisting of phenylene and    pyridinylene, which are each optionally substituted with one or two    substituents independently selected from F, Cl, —O—CH₃ and CH₃;-   R¹ independently of one another are selected from the group R¹-G1    consisting of halogen, CN, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl,    —O—(C₁₋₆-alkyl), —S—(C₁₋₃-alkyl), —O—(C₃₋₆-cycloalkyl),    —O—(C₅₋₆-cycloalkenyl), —O—(CH₂)₁₋₂—(C₃₋₆-cycloalkyl),    —O—(C₁₋₃-alkyl)-aryl, —O—CH₂—(C₂₋₄-alkenyl), —O—CH₂—(C₂₋₄-alkinyl),    —O—CH₂-heterocyclyl, —O—CH₂-heteroaryl, —O-heterocyclyl, —O-aryl,    —O-heteroaryl, —(C═O)—NH-aryl, —NR^(N1)R^(N2),

-   -   wherein R^(N1) is H, —CD₃, or C₁₋₃-alkyl, and    -   R^(N2) is H, —CD₃, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,        —(CH₂)₁₋₂—(C₃₋₆-cycloalkyl), heterocyclyl, —CH₂-heterocyclyl, or        aryl,    -   or wherein R^(N1) and R^(N2) are connected and together with the        N-atom to which they are attached form an azetidinyl,        pyrrolidinyl, piperidinyl, 2,5-dihydro-1H-pyrrolyl, morpholinyl,        thiomorpholinyl, or [1,4]oxazepanyl ring, wherein each of said        rings is optionally substituted with one to four F, or one or        two CN, OH, C₁₋₃-alkyl, —O—C₁₋₃-alkyl or        —(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl), said substituents being the same        or different,        -   wherein heterocyclyl is tetrahydrofuranyl or            tetrahydropyranyl, wherein heteroaryl is selected from the            group consisting of pyridinyl, pyrimidinyl, pyridazinyl and            pyrazinyl,        -   wherein aryl is selected from the group consisting of            phenyl, indanyl and naphthyl,        -   wherein each alkyl is linear or branched and is optionally            substituted with 1 to 6 F or with one or two CN, —OH,            —O—(C₁₋₄-alkyl) or phenyl,        -   wherein each cycloalkyl is optionally substituted with 1 to            4 F or with one CN, OH, CH₃, CF₃ or —SO₂—(C₁₋₃-alkyl), and        -   wherein each aryl or heteroaryl is optionally substituted            with one or two substituents independently selected from F,            C₁₋₃-alkyl or —O—(C₁₋₃-alkyl);

-   n is 1, 2 or 3;

-   R² is selected from the group R²-G1 consisting of H, F, Cl, CN and    —O—(C₁₋₃-alkyl);

-   R³ is selected from the group R³-G1 consisting of H and C₁₋₃-alkyl;

-   L is selected from the group L-G1 consisting of straight-chain    C₁₋₃-alkylene, which is optionally substituted with one or two    C₁₋₃-alkyl groups; and

-   T is selected from the group T-G1 consisting of: H,    -   linear or branched C₁₋₆-alkyl which is optionally substituted        with one to six F, with one CN, OH, —O—CH₃ or —O—C(═O)—CH₃, or        with a heteroaryl group preferably selected from the group        consisting of: oxazolyl, thiazolyl, pyrrolyl, pyrazolyl,        isoxazolyl, isothiazolyl, pyrimidinyl and pyrazinyl,        -   wherein each of said heteroaryl groups is optionally            substituted with one or two substituents, which are            independently of each other selected from the group            consisting of C₁₋₃-alkyl, —(C₁₋₃-alkyl)-O—CH₃ and            —NH—(C═O)—(C₁₋₃-alkyl);    -   C₃₋₆-cycloalkyl which is optionally substituted with one or two        F, CN, C₁₋₃-alkyl, CF₃, OH, —O—(C₁₋₃-alkyl), —NH₂,        —NH—(C═O)—(C₁₋₃-alkyl), —NH—(C═O)—(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl),        —NH—(C═O)—O—(C₁₋₆-alkyl), —C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl) or        —C(═O)—N(C₁₋₃-alkyl)₂, wherein the substituents are identical or        different;    -   —O—(C₁₋₄-alkyl) which is optionally substituted with        C₃₋₇-cycloalkyl;    -   NR⁴R⁵, wherein R⁴ is H or C₁₋₃-alkyl, and R⁵ is H, C₁₋₃-alkyl,        —(C₁₋₃-alkyl)-O—CH₃ or a 5-membered heteroaryl group containing        1 to 3 heteroatoms selected independently from O, S, N and NH,        wherein said heteroaryl group is optionally substituted with        C₁₋₃-alkyl; or wherein R⁴ and R⁵ are connected and together with        the N to which they are attached form an azetidinyl,        pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring that        is optionally substituted with one or two C₁₋₃-alkyl or with one        —NH—(C═O)—CH₃; and    -   a 5-membered heteroaryl group containing one to three        heteroatoms selected independently from O, S, N and NH, which is        optionally substituted with one or two substituents selected        independently from the group consisting of: C₁₋₃-alkyl, —NH₂,        —NH—C(═O)—C₁₋₃-alkyl, —NH—C(═O)—(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl),        —NH—C(═O)—(C₁₋₃-alkyl)-OH, —NH—C(═O)—O—(C₁₋₆-alkyl) and        —O—(C₁₋₂-alkyl), wherein each alkyl group is optionally        substituted with one to three F or with one OH;

-   a tautomer or stereoisomers thereof,    or a salt thereof,    or a solvate or hydrate thereof.

In a further aspect the present invention relates to processes forpreparing a compound of general formula (I) and to new intermediatecompounds in these processes.

A further aspect of the invention relates to a salt of the compounds ofgeneral formula (I) according to this invention, in particular to apharmaceutically acceptable salt thereof.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula (I) orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are mediated by inhibiting the activity ofacetyl-CoA carboxylase(s) in a patient in need thereof characterized inthat a compound of general formula (I) or a pharmaceutically acceptablesalt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder in a patient in needthereof characterized in that a compound of general formula (I) or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a cardiovascular disease or disorder in a patient in needthereof characterized in that a compound of general formula (I) or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a neurodegenerative disease or disorder or for treating adisease or disorder of the central nervous system in a patient in needthereof characterized in that a compound of general formula (I) or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a cancer, a malignant disorder or a neoplasia in a patientin need thereof characterized in that a compound of general formula (I)or a pharmaceutically acceptable salt thereof is administered to thepatient.

According to another aspect of the invention, there is provided the useof a compound of the general formula (I) or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament for atherapeutic method as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula (I) or a pharmaceutically acceptablesalt thereof for a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition mediated by the inhibition of acetyl-CoAcarboxylase(s) in a patient that includes the step of administering tothe patient in need of such treatment a therapeutically effective amountof a compound of the general formula (I) or a pharmaceuticallyacceptable salt thereof in combination with a therapeutically effectiveamount of one or more additional therapeutic agents.

In a further aspect this invention relates to a use of a compound of thegeneral formula (I) or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment or prevention of diseases or conditions which are mediated bythe inhibition of acetyl-CoA carboxylase(s).

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula (I)or a pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents,particularly Ar, R¹, R², R³, R⁴, L, T and n, are defined as above andhereinafter. If residues, substituents, or groups occur several times ina compound, as for example R¹, they may have the same or differentmeanings. Some preferred meanings of individual groups and substituentsof the compounds according to the invention will be given hereinafter.Any and each of these definitions may be combined with each other.

Ar: Ar-G1:

The group Ar is preferably selected from the group Ar-G1 as definedhereinbefore and hereinafter.

Ar-G2:

In another embodiment the group Ar is selected from the group Ar-G2consisting of: phenylene, which is optionally monosubstituted with F.

Ar-G3:

In another embodiment the group Ar is selected from the group Ar-G3consisting of: phenylene.

Ar-G4:

In another embodiment the group Ar is selected from the group Ar-G4consisting of:

wherein the before mentioned group is optionally monosubstituted with F.

Ar-G5:

In another embodiment the group Ar is selected from the group Ar-G5consisting of:

R¹: R¹-G1:

The group R¹ is preferably selected from the group R¹-G1 as definedhereinbefore and hereinafter.

R¹-G2:

In another embodiment the group R¹ is independently of one anotherselected from the group R¹-G2 consisting of:

F, Cl, Br, CN, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, phenyl, —O—(C₁₋₅-alkyl),—O—(C₃₋₆-cycloalkyl), —O—(C₅₋₆-cycloalkenyl),—O—(CH₂)₁₋₂—(C₃₋₆-cycloalkyl), —O—(C₁₋₂-alkyl)-phenyl,—O—CH₂—(C₂₋₄-alkenyl), —O—CH₂-heterocyclyl, —O—CH₂-pyridinyl,—O-heterocyclyl, —O-phenyl, —O-pyridinyl, —NR^(N1)R^(N2) and

wherein R^(N1) is H, —CD₃, or C₁₋₃-alkyl, andR^(N2) is —CD₃, C₁₋₅-alkyl, C₃₋₆-cycloalkyl, —CH₂—(C₃₋₆-cycloalkyl),heterocyclyl, —CH₂-heterocyclyl or phenyl,or wherein R^(N1) and R^(N2) are connected and together with the N-atomto which they are attached form an azetidinyl, pyrrolidinyl,piperidinyl, 2,5-dihydro-1H-pyrrolyl, morpholinyl, thiomorpholinyl or[1,4]oxazepanyl ring, wherein each of said rings is optionallysubstituted with one to four F or with one or two CN, OH, C₁₋₃-alkyl,—O—C₁₋₃-alkyl, or —C₁₋₃-alkyl-O—C₁₋₃-alkyl, said substituents being thesame or different,

-   -   wherein heterocyclyl is tetrahydrofuranyl or tetrahydropyranyl,    -   wherein each alkyl is linear or branched and is optionally        substituted with 1 to 6 F or with one or two CN, —OH,        —O—(C₁₋₄-alkyl) or phenyl,    -   wherein each cycloalkyl is optionally substituted with 1 to 4 F        or with one CN, OH, CH₃ or —SO₂—CH₃, and    -   wherein each phenyl is optionally substituted with one F, Cl or        —O—(C₁₋₃-alkyl).

R¹-G3:

In another embodiment the group R¹ is selected from the group R¹-G3consisting of: F, Cl, CN, C₁₋₄-alkyl, C₃₋₅-cycloalkyl, phenyl,—O—(C₁₋₅-alkyl), —O—(C₃₋₆-cycloalkyl), —O-tetrahydrofuranyl,—O—CH₂—(C₃₋₄-cycloalkyl), —NR^(N1)R^(N2) and

wherein R^(N1) is H, —CD₃, or C₁₋₂-alkyl, andR^(N2) is —CD₃, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, or —CH₂—(C₃₋₆-cycloalkyl),or wherein R^(N1) and R^(N2) are connected and together with the N-atomto which they are attached form an azetidinyl, pyrrolidinyl, piperidinylor morpholinyl ring, wherein each of said rings is optionallysubstituted with one or two F, OH or CH₃, said substituents being thesame or different,

-   -   wherein each alkyl is linear or branched and is optionally        substituted with 1 to 3 F or with one —O—CH₃ or OH;    -   wherein each C₃₋₆-cycloalkyl is optionally substituted with 1 to        2 F or with one CN, OH or CH₃; and    -   wherein each phenyl is optionally substituted with one —O—CH₃.

R¹-G4:

In another embodiment the group R¹ is selected from the group R¹-G4consisting of: F, Cl, Br, CN, C₁₋₄-alkyl, —O—(C₁₋₅-alkyl),—O—(C₃₋₆-cycloalkyl), —O-pyridinyl, —NR^(N1)R^(N2),

wherein R^(N1) is H, —CD₃ or C₁₋₂-alkyl, andR^(N2) is —CD₃, C₁₋₅-alkyl or C₃₋₆-cycloalkyl,

-   -   wherein each alkyl is linear or branched and is optionally        substituted with 1 to 3 F or with one or two CN, OH,        —O—(C₁₋₃-alkyl) or phenyl.

R¹-G4a:

In another embodiment the group R¹ is selected from the group R¹-G4aconsisting of: C₁₋₄-alkyl, —O—(C₁₋₅-alkyl), —O—(C₃₋₆-cycloalkyl),—O-pyridinyl, —NR^(N1)R^(N2),

wherein R^(N1) is H, —CD₃ or C₁₋₂-alkyl, andR^(N2) is —CD₃, C₁₋₅-alkyl or C₃₋₆-cycloalkyl,

-   -   wherein each alkyl is linear or branched and is optionally        substituted with 1 to 3 F or with one or two CN, OH,        —O—(C₁₋₃-alkyl) or phenyl;        or, if n is 2, the second R¹ group is selected from the group        consisting of F, Cl, Br, CN, CH₃ and —O—CH₃;        or, if n is 3, the third R¹ group is F.

Preferably, n is 1 or 2.

R¹-G4b:

In another embodiment the group R¹ is selected from the group R¹-G4bconsisting of: —O—(C₁₋₅-alkyl), —O—(C₃₋₆-cycloalkyl), —O-pyridinyl,—NR^(N1)R^(N2),

wherein R^(N1) is H, —CD₃ or C₁₋₂-alkyl, andR^(N2) is —CD₃, C₁₋₅-alkyl or C₃₋₆-cycloalkyl,

-   -   wherein each alkyl is linear or branched and is optionally        substituted with 1 to 3 F or with one or two CN, OH,        —O—(C₁₋₃-alkyl) or phenyl;        or, if n is 2, the second R¹ group is selected from the group        consisting of F, Cl, Br, CN, CH₃ and —O—CH₃;        or, if n is 3, the third R¹ group is F.

Preferably, n is 1 or 2.

R¹-G5:

In another embodiment the group R¹ is selected from the group R¹-G5consisting of:

F, Cl;

—O—(C₁₋₅-alkyl), which is optionally substituted with 1-3 F or one OH;—O—CH₂—(C₃₋₅-cycloalkyl), which is optionally substituted with 1-2 F;—O—(C₃₋₆-cycloalkyl);—NR^(N1)R^(N2), wherein R^(N2) is H or C₁₋₂-alkyl; and R^(N2) isC₁₋₄-alkyl or C₃₋₆-cycloalkyl, wherein each alkyl is optionallysubstituted with 1 to 3 F or with one OH or —O—CH₃;

R¹-G5a:

In another embodiment the group R¹ is selected from the group R¹-G5aconsisting of:

—O—(C₁₋₅-alkyl), which is optionally substituted with 1-3 F or one OH;—O—CH₂—(C₃₋₅-cycloalkyl), which is optionally substituted with 1-2 F;—O—(C₃₋₆-cycloalkyl);—NR^(N1)R^(N2), wherein R^(N1) is H or C₁₋₂-alkyl; and R^(N2) isC₁₋₄-alkyl or C₃₋₆-cycloalkyl, wherein each alkyl is optionallysubstituted with 1 to 3 F or with one OH or —O—CH₃;

or, if n is 2, the second R¹ group is selected from the group consistingof F, Cl, Br, CN, CH₃ and —O—CH₃;or, if n is 3, the third R¹ group is F.

Preferably, n is 1 or 2.

R¹-G6:

In another embodiment the group R¹ is selected from the group R¹-G6consisting of: F, Cl, —O—(C₁₋₅-alkyl),

R¹-G6a:

In another embodiment the group R¹ is selected from the group R¹-G6aconsisting of: F, Cl, —O—(C₁₋₅-alkyl),

or, if n is 2, the second R¹ group is selected from the group consistingof F, Cl, Br, CN, CH₃ and —O—CH₃;or, if n is 3, the third R¹ group is F.

Preferably, n is 1 or 2.

n

n is 1, 2 or 3.

Preferably, n is 1 or 2.

In one embodiment, n is 2.

In another embodiment, n is 1.

R² R²-G1:

The group R² is preferably selected from the group R²-G1 as definedhereinbefore and hereinafter.

R²-G2:

In another embodiment the group R² is selected from the group R²-G2consisting of: H, F and —O—CH₃.

R²-G3:

In another embodiment, the group R² is selected from the group R²-G3consisting of H.

R³: R³-G1:

The group R³ is preferably selected from the group R³-G1 as definedhereinbefore and hereinafter.

R³-G2:

In one embodiment the group R³ is selected from the group R³-G2consisting of H and CH₃.

R³-G3:

In another embodiment the group R³ is selected from the group R³-G3consisting of H.

L: L-G1:

The group L is preferably selected from the group L-G1 as definedhereinbefore and hereinafter.

L-G2:

In one embodiment the group L is selected from the group L-G2 consistingof: a straight-chain C₁₋₃-alkylene group which is optionally substitutedwith one or two CH₃ groups.

L-G3:

In another embodiment the group L is selected from the group L-G3consisting of: a straight-chain C₁₋₂-alkylene group which is optionallysubstituted with one methyl group.

L-G4:

In another embodiment the group L is selected from the group L-G4consisting of:

wherein m is 0 or 1, andwherein the asterisk to the left-hand side is connected to Ar and theasterisk to the right-hand side is connected to N atom depicted informula (I).

L-G5:

In another embodiment the group L is selected from the group L-G5consisting of: —CH(CH₃)—.

L-G5a:

In another embodiment the group L is selected from the group L-G5aconsisting of:

wherein the asterisk to the left-hand side is connected to Ar and theasterisk to the right-hand side is connected to N atom depicted informula (I).

L-G5b:

In another embodiment the group L is selected from the group L-G5bconsisting of:

wherein the asterisk to the left-hand side is connected to Ar and theasterisk to the right-hand side is connected to N atom depicted informula (I).

T: T-G1:

The group T is preferably selected from the group T-G1 as definedhereinbefore and hereinafter.

T-G2:

In one embodiment the group T is selected from the group T-G2 consistingof:

H,

linear or branched C₁₋₄-alkyl which is optionally substituted with oneto six F, or with one CN, —O—CH₃ or OH or with a heteroaryl grouppreferably selected from the group consisting of: oxazolyl, thiazolyl,pyrrolyl, isoxazolyl, pyrimidinyl and pyrazinyl,

-   -   wherein each of said heteroaryl groups is optionally substituted        with one or two substituents, which are independently of each        other selected from the group consisting of C₁₋₃-alkyl,        —(C₁₋₃-alkyl)-O—CH₃ and —NH—(C═O)—(C₁₋₃-alkyl);        C₃₋₆-cycloalkyl which is optionally substituted with one or two        F, CN, C₁₋₃-alkyl, CF₃, —NH—(C═O)—(C₁₋₃-alkyl),        —NH—(C═O)—(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl) or        —NH—(C═O)—O—(C₁₋₄-alkyl), wherein the substituents are identical        or different;        —O—(C₁₋₃-alkyl) which is optionally substituted with one        C₃₋₅-cycloalkyl;        —NR⁴R⁵, wherein R⁴ is H or C₁₋₃-alkyl, and R⁵ is H, C₁₋₃-alkyl,        —(C₁₋₃-alkyl)-O—CH₃ or a 5-membered heteroaryl group containing        1 to 3 heteroatoms selected independently from O, S, N and NH,        which is preferably selected from the group consisting of:        oxazolyl, thiazolyl, pyrrolyl, isoxazolyl, isothiazolyl and        imidazolyl; or wherein R⁴ and R⁵ are connected and together with        the N to which they are attached form an azetidinyl,        pyrrolidinyl, piperidinyl or morpholinyl ring that is optionally        substituted with one or two C₁₋₃-alkyl or with one        —NH—(C═O)—CH₃; and        a 5-membered heteroaryl group containing one to three        heteroatoms selected independently from O, S, N and NH, which is        optionally substituted with one or two substituents selected        independently from the group consisting of C₁₋₃-alkyl,        —O—(C₁₋₂-alkyl), —NH—C(═O)—C₁₋₃-alkyl and        —NH—C(═O)—(C₁₋₃-alkyl)-O—CH₃.

T-G3:

In one embodiment the group T is selected from the group T-G3 consistingof:

linear or branched C₁₋₃-alkyl which is optionally substituted with oneto six F, or with one CN, OH or —O—CH₃, or with a heteroaryl grouppreferably selected from the group consisting of thiazolyl, isoxazolyland pyrimidinyl,

-   -   wherein each of said heteroaryl groups is optionally substituted        with one or two substituents, which are independently of each        other selected from the group consisting of C₁₋₃-alkyl,        —(C₁₋₃-alkyl)-O—CH₃ and —NH—(C═O)—CH₃;        C₃₋₆-cycloalkyl which is optionally substituted with one or two        F or one CN, CF₃, C₁₋₃-alkyl, —NH—(C═O)—(C₁₋₃-alkyl),        —NH—(C═O)—(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl) or        —NH—(C═O)—O—(C₁₋₄-alkyl);        —O—(C₁₋₃-alkyl) which is optionally substituted with one        cyclopropyl;        —NR⁴R⁵, wherein R⁴ is H or C₁₋₃-alkyl, and R⁵ is H, C₁₋₃-alkyl,        —(C₁₋₃-alkyl)-O—CH₃ or isoxazolyl; or wherein R⁴ and R⁵ are        connected and together with the N to which they are attached        form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl        ring that is optionally substituted with one or two C₁₋₃-alkyl        or with one —NH—(C═O)—CH₃; and        a furanyl, thiazolyl, oxazolyl, pyrazolyl, isoxazolyl,        isothiazolyl or thiadiazolyl group, each of which is optionally        substituted with one or two substituents selected independently        from the group consisting of C₁₋₃-alkyl,        —NH—C(═O)—(C₁₋₃-alkyl)-O—CH₃ and —NH—C(═O)—C₁₋₃-alkyl.

T-G4:

In one embodiment the group T is selected from the group T-G4 consistingof:

linear or branched C₁₋₃-alkyl which is optionally substituted with oneto three F,C₃₋₆-cycloalkyl which is optionally substituted with one F, CH₃,—NH—(C═O)—CH₃, —NH—(C═O)—CH₂—O—CH₃ or —NH—(C═O)—O—(C₁₋₄-alkyl);—O—(C₁₋₂-alkyl) which is optionally substituted with one cyclopropyl;—NR⁴R⁵, wherein R⁴ is H or C₁₋₃-alkyl, and R⁵ is C₁₋₃-alkyl orisoxazolyl; or wherein R⁴ and R⁵ are connected and together with the Nto which they are attached form an azetidinyl, pyrrolidinyl, piperidinylor morpholinyl ring; andA furanyl, thiazolyl, oxazolyl, pyrazolyl, isoxazolyl or isothiazolylgroup, each of which is optionally substituted with one or twosubstituents selected independently from the group consisting of CH₃,—NH—C(═O)—CH₂—O—CH₃, —NH—C(═O)—CH₃ and —NH—C(═O)—CH₂CH₃.

T-G4a:

In one embodiment the group T is selected from the group T-G4aconsisting of:

linear or branched C₁₋₃-alkyl which is optionally substituted with oneto three F,C₃₋₆-cycloalkyl which is optionally substituted with one CH₃,—NH—(C═O)—CH₃, —NH—(C═O)—CH₂—O—CH₃ or —NH—(C═O)—O—(C₁₋₄-alkyl);—O—(C₁₋₂-alkyl) which is optionally substituted with one cyclopropyl;—NR⁴R⁵, wherein R⁴ is H or C₁₋₃-alkyl, and R⁵ is C₁₋₃-alkyl orisoxazolyl; or wherein R⁴ and R⁵ are connected and together with the Nto which they are attached form an azetidinyl, pyrrolidinyl, piperidinylor morpholinyl ring; anda thiazolyl, oxazolyl, pyrazolyl, isoxazolyl or isothiazolyl group, eachof which is optionally substituted with one or two substituents selectedindependently from the group consisting of CH₃, —NH—C(═O)—CH₂—O—CH₃ and—NH—C(═O)—CH₃.

T-G5:

In one embodiment the group T is selected from the group T-G5 consistingof:

linear or branched C₁₋₃-alkyl which is optionally substituted with oneto three F;

—NH₂, wherein each H is optionally independently of each other replacedwith methyl or ethyl;

anda 5-membered heteroaryl group selected from:

T-G5a:

In one embodiment the group T is selected from the group T-G5aconsisting of:

linear or branched C₁₋₃-alkyl which is optionally substituted with oneto three F;

—NH₂, wherein each H is optionally independently of each other replacedwith methyl or ethyl;

anda 5-membered heteroaryl group selected from:

T-G6:

In one embodiment the group T is selected from the group T-G6 consistingof: —CH₃, —CHF₂, —CH₂CH₃, —N(CH₃)₂, —OCH₃,

T-G6a:

In one embodiment the group T is selected from the group T-G6aconsisting of: —CH₃, —CHF₂, —CH₂CH₃, —N(CH₃)₂, —OCH₃,

T-G7:

In one embodiment the group T is selected from the group T-G7 consistingof: CH₃.

Examples of preferred subgeneric embodiments according to the presentinvention are set forth in the following table, wherein each substituentgroup of each embodiment is defined according to the definitions setforth hereinbefore and wherein all other substituents of the formula (I)are defined according to the definitions set forth hereinbefore:

Embod- iment R¹ Ar R² L R³ T n E-1 R¹-G1 Ar-G2 R²-G2 L-G2 R³-G2 T-G1 1,2 or 3 E-2 R¹-G2 Ar-G2 R²-G2 L-G3 R³-G2 T-G2 1, 2 or 3 E-3 R¹-G3 Ar-G3R²-G3 L-G3 R³-G3 T-G3 1, 2 or 3 E-4 R¹-G4 Ar-G3 R²-G3 L-G5 R³-G3 T-G3 1,2 or 3 E-5 R¹-G4a Ar-G3 R²-G3 L-G5 R³-G3 T-G3 1, 2 or 3 E-6 R¹-G3 Ar-G4R²-G3 L-G5 R³-G3 T-G4 1 or 2 E-7 R¹-G4 Ar-G4 R²-G3 L-G5 R³-G3 T-G6 1 or2 E-8 R¹-G4a Ar-G4 R²-G3 L-G5 R³-G3 T-G7 1 or 2 E-9 R¹-G3 Ar-G5 R²-G3L-G5 R³-G3 T-G4 1 or 2 E-10 R¹-G4 Ar-G5 R²-G3 L-G5 R³-G3 T-G6 1 or 2E-11 R¹-G4a Ar-G5 R²-G3 L-G5 R³-G3 T-G7 1 or 2 E-12 R¹-G5 Ar-G3 R²-G3L-G5 R³-G3 T-G3 1 or 2 E-13 R¹-G5a Ar-G5 R²-G3 L-G5 R³-G3 T-G4 1 or 2E-14 R¹-G5a Ar-G5 R²-G3 L-G5 R³-G3 T-G5 1 or 2 E-15 R¹-G6 Ar-G3 R²-G3L-G5 R³-G3 T-G3 1 or 2 E-16 R¹-G6a Ar-G5 R²-G3 L-G5 R³-G3 T-G4 1 or 2E-17 R¹-G6a Ar-G5 R²-G3 L-G5 R³-G3 T-G5 1 or 2

The following preferred embodiments of compounds of the formula (I) aredescribed using generic formulae (I.1a) to (I.4c), wherein any tautomersand stereoisomers, solvates, hydrates and salts thereof, in particularthe pharmaceutically acceptable salts thereof, are encompassed.

wherein in each of the above formulae (I.1a) to (I.4c), the groups Ar,R¹, R², R³, L, T and n are defined as hereinbefore and hereinafter.

Examples of preferred subgeneric embodiments according to the presentinvention are set forth in the following table, wherein each substituentgroup of each embodiment is defined according to the definitions setforth hereinbefore and wherein all other substituents of the formula Iare defined according to the definitions set forth hereinbefore:

Embodiment Formula R¹ Ar R² L R³ T n E-18 (I.1a) R¹-G3 Ar-G3 R²-G2 L-G2R³-G2 T-G2 1, 2 or 3 E-19 (I.1a) R¹-G4 Ar-G3 R²-G2 L-G3 R³-G2 T-G5 1, 2or 3 E-20 (I.1a) R¹-G4a Ar-G3 R²-G3 L-G3 R³-G3 T-G5 1, 2 or 3 E-21(I.1a) R¹-G5 Ar-G3 R²-G3 L-G3 R³-G2 T-G5 1, 2 or 3 E-22 (I.1a) R¹-G5aAr-G3 R²-G3 L-G3 R³-G3 T-G5 1, 2 or 3 E-23 (I.1b) R¹-G3 Ar-G3 R²-G3 L-G2R³-G2 T-G3 1, 2 or 3 E-24 (I.1b) R¹-G4 Ar-G3 R²-G3 L-G3 R³-G2 T-G5 1, 2or 3 E-25 (I.1b) R¹-G4a Ar-G3 R²-G3 L-G3 R³-G3 T-G5 1, 2 or 3 E-26(I.1b) R¹-G5 Ar-G3 R²-G3 L-G3 R³-G2 T-G5 1, 2 or 3 E-27 (I.1b) R¹-G5aAr-G3 R²-G3 L-G3 R³-G3 T-G5 1, 2 or 3 E-28 (I.2a) R¹-G3 — R²-G2 — — T-G21 or 2 E-29 (I.2a) R¹-G4 — R²-G2 — — T-G5 1 or 2 E-30 (I.2a) R¹-G4a —R²-G3 — — T-G5 1 or 2 E-31 (I.2a) R¹-G5 — R²-G2 — — T-G5 1 or 2 E-32(I.2a) R¹-G5a — R²-G3 — — T-G5 1 or 2 E-33 (I.2b) R¹-G3 — R²-G2 — — T-G31 or 2 E-34 (I.2b) R¹-G4 — R²-G2 — — T-G5 1 or 2 E-35 (I.2b) R¹-G4a —R²-G3 — — T-G5 1 or 2 E-36 (I.2b) R¹-G5 — R²-G2 — — T-G5 1 or 2 E-37(I.2b) R¹-G5a — R²-G3 — — T-G5 1 or 2 E-38 (I.3a) R¹-G4a — R²-G3 — —T-G4 1 or 2 E-39 (I.4a) R¹-G5a — R²-G3 — — T-G6 1 or 2

A preferred embodiment of the present invention concerns compounds ofgeneral formula

whereinn is 1 or 2 or 3;R¹ is selected from a group consisting of C₁₋₄-alkyl, —O—(C₁₋₅-alkyl),—O—(C₃₋₆-cycloalkyl), —O-pyridinyl, —NR^(N1)R^(N2),

wherein R^(N1) is H or C₁₋₂-alkyl, and R^(N2) is C₁₋₅-alkyl orC₃₋₆-cycloalkyl,

-   -   wherein each alkyl is linear or branched and is optionally        substituted with 1 to 3 F or with one or two CN, OH,        —O—(C₁₋₃-alkyl) or phenyl;        or, if n is 2, the second R¹ group is selected from the group        consisting of F, Cl, Br, CN, CH₃ and —O—CH₃;

R² is H; and

T is selected from a group consisting of:linear or branched C₁₋₃-alkyl which is optionally substituted with oneto three F,C₃₋₆-cycloalkyl which is optionally substituted with one F, CH₃,—NH—(C═O)—CH₃, —NH—(C═O)—CH₂—O—CH₃ or —NH—(C═O)—O—(C₁₋₄-alkyl);—O—(C₁₋₂-alkyl) which is optionally substituted with one cyclopropyl;—NR⁴R⁵, wherein R⁴ is H or C₁₋₃-alkyl, and R⁵ is C₁₋₃-alkyl orisoxazolyl; or wherein R⁴ and R⁵ are connected and together with the Nto which they are attached form an azetidinyl, pyrrolidinyl, piperidinylor morpholinyl ring; anda furanyl, thiazolyl, oxazolyl, pyrazolyl, isoxazolyl or isothiazolylgroup, each of which is optionally substituted with one or twosubstituents selected independently from the group consisting of CH₃,—NH—C(═O)—CH₂—O—CH₃, —NH—C(═O)—CH₃ and —NH—C(═O)—CH₂CH₃;or a salt thereof.

A preferred embodiment of the present invention concerns compounds ofgeneral formula

whereinn is 1 or 2;R¹ is selected from a group consisting of:—O—(C₁₋₅-alkyl), which is optionally substituted with 1-3 F or one OH;—O—CH₂—(C₃₋₅-cycloalkyl), which is optionally substituted with 1-2 F;—O—(C₃₋₆-cycloalkyl);—NR^(N1)R^(N2), wherein R^(N1) is H or C₁₋₂-alkyl; and R^(N2) is —CD₃,C₁₋₄-alkyl or C₃₋₆-cycloalkyl, wherein each alkyl is optionallysubstituted with 1 to 3 F or with one OH or —O—CH₃;

or, if n is 2, the second R¹ group is selected from the group consistingof F, Cl, Br, CN, CH₃ and —O—CH₃;

R² is H; and

T is selected from a group consisting of:

—CH₃, —CHF₂, —CH₂CH₃, —N(CH₃)₂, —OCH₃,

or a pharmaceutically acceptable salt thereof.

Preferred compounds of the invention include:

and the pharmaceutically acceptable salts thereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The compounds according to the invention may be obtained using methodsof synthesis which are known to the one skilled in the art and describedin the literature of organic synthesis. Preferably, the compounds areobtained analogously to the methods of preparation explained more fullyhereinafter, in particular as described in the experimental section.

TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula (I)”, “compound(s) of the invention” and the like denote thecompounds of the formula (I) according to the present inventionincluding their tautomers, stereoisomers and mixtures thereof and thesalts thereof, in particular the pharmaceutically acceptable saltsthereof, and the solvates and hydrates of such compounds, including thesolvates and hydrates of such tautomers, stereoisomers and saltsthereof.

The terms “treatment” and “treating” embraces both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein,unless otherwise indicated, refers to the inhibition of acetyl-CoAcarboxylase(s) (ACC) with one or more compounds of the presentinvention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refers to the (i) treatment, including preventionthe particular disease or condition, (ii) attenuation, amelioration, orelimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk is may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or to the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex).” or the like means thatin each of the before mentioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

In the following the term bicyclic includes spirocyclic.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present inventionalso comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 1 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either aloneor in combination with another radical, denotes an acyclic, straight orbranched chain divalent alkyl radical containing from 1 to n carbonatoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)- and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkenylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenylene includes —CH═CH—,—CH═CH—CH₂—, —CH₂—CH═CH—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(2-n)-alkynylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynylene includes —C≡C—,—C≡C—CH₂—, —CH₂—C≡C—.

The term “C_(3-n)-carbocyclyl” as used either alone or in combinationwith another radical, denotes a monocyclic, bicyclic or tricyclic,saturated or unsaturated hydrocarbon radical with 3 to n C atoms. Thehydrocarbon radical is preferably nonaromatic. Preferably the 3 to n Catoms form one or two rings. In case of a bicyclic or tricyclic ringsystem the rings may be attached to each other via a single bond or maybe fused or may form a spirocyclic or bridged ring system. For examplethe term C₃₋₁₀-carbocyclyl includes C₃₋₁₀-cylcoalkyl,C₃₋₁₀-cycloalkenyl, octahydro-pentalenyl, octahydroindenyl,decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably, theterm C_(3-n)-carbocyclyldenotes C_(3-n)-cylcoalkyl, in particularC₃₋₇-cycloalkyl.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term “C_(3-n)-cycloalkenyl”, wherein n is an integer 3 to n, eitheralone or in combination with another radical, denotes a cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl. More preferably, the term “aryl” as used herein, eitheralone or in combination with another radical, denotes phenyl ornaphthyl, most preferably phenyl.

The term “heterocyclyl” means a saturated or unsaturated mono-, bi-,tri- or spirocarbocyclic, preferably mono-, bi- or spirocyclic-ringsystem containing one or more heteroatoms selected from N, O or S(O)_(r)with r=0, 1 or 2, which in addition may have a carbonyl group. Morepreferably, the term “heterocyclyl” as used herein, either alone or incombination with another radical, means a saturated or unsaturated, evenmore preferably, a saturated mono-, bi- or spirocyclic-ring systemcontaining 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2 which in addition may have a carbonyl group. The term“heterocyclyl is intended to include all the possible isomeric forms.Examples of such groups include aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl,piperazinonyl, morpholinonyl.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “heteroaryl” means a mono- or polycyclic, preferably mono- orbicyclic-ring system containing one or more heteroatoms selected from N,O or S(O)_(r) with r=0, 1 or 2 wherein at least one of the heteroatomsis part of an aromatic ring, and wherein said ring system may have acarbonyl group. More preferably, the term “heteroaryl” as used herein,either alone or in combination with another radical, means a mono- orbicyclic-ring system containing 1, 2, 3 or 4 heteroatoms selected fromN, O or S(O)_(r) with r=0, 1 or 2 wherein at least one of theheteroatoms is part of an aromatic ring, and wherein said ring systemmay have a carbonyl group. The term “heteroaryl” is intended to includeall the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

All rests and substituents as defined hereinbefore and hereinafter maybe substituted with one or more F atoms.

Pharmacological Activity

The activity of the compounds of the invention may be demonstrated usingthe following ACC2 assay:

Spectrophotometric 384 Well Assay

Malonyl CoA formation by acetyl CoA carboxylases is stoichometricallylinked to the consumption of ATP. ACC2 activity is measured in aNADH-linked kinetic method measuring ADP generated during the ACCreaction using a coupled lactate dehydrogenase/pyruvate kinase reaction.

For biological testing, a human ACC2 construct which lacks the 128 aminoacids at the N-terminus for increased solubility (nt 385-6966 in Genbankentry AJ575592) is cloned. The protein is then expressed in insect cellsusing a baculoviral expression system. Protein purification is performedby anion exchange.

All compounds are dissolved in dimethyl sulfoxide (DMSO) to aconcentration of 10 mM.

Assay reactions are then carried out in 384-well plates, with hACC2 inan appropriate dilution and at final assay concentrations (f.c.) of 100mM Tris (pH 7.5), 10 mM trisodium citrate, 25 mM KHCO₃, 10 mM MgCl₂, 0.5mg/ml BSA, 3.75 mM reduced L-glutathione, 15 U/ml lactate dehydrogenase,0.5 mM phosphoenolpyruvate, 15 U/ml pyruvate kinase, compounds atdifferent concentrations at final DMSO concentrations of 1%.

The enzymatic reaction is then started by addition of a mixture of NADH,acetyl Coenzyme A (both 200 μM f.c.) and ATP (500 uM f.c.). The decreaseof the optical density (slope S) is then determined at 25° C. at awavelength of 340 nm over 15 minutes in a spectrophotometric reader.

Each assay microtiter plate contains wells with vehicle instead ofcompound as controls for the non-inhibited enzyme (100% CTL; ‘HIGH’) andwells without acetyl-CoA as controls for non-specific NADH degradation(0% CTL; ‘LOW’).

The slope S is used for calculation of %CTL=(S(compound)−S(‘LOW’))/(S(‘HIGH’)−S(‘LOW’))*100. Compounds will givevalues between 100% CTL (no inhibition) and 0% CTL (completeinhibition).

For IC₅₀ value determination, the sample slope in the presence of thetest compound after subtraction of the low controls(S(compound)−S(‘LOW’)) are used.

An IC₅₀ value is derived from the compound slopes at different dosagesafter subtraction of the low controls (S(compound)−S(‘LOW’)) bynon-linear regression curve fitting (equationy=(A+((B−A)/(1+((C/x)̂D))))).

The compounds of general formula (I) according to the invention forexample have IC₅₀ values below 5000 nM, particularly below 1000 nM,preferably below 300 nM, most preferably below 100 nM.

In the following table the activity expressed as IC₅₀ (μM) of compoundsaccording to the invention is presented wherein the IC₅₀ values aredetermined in the ACC2 assay as described hereinbefore. The term“Example” refers to the example numbers according to the followingexperimental section.

Example IC₅₀ [μM] 1.1 0.489 1.2 0.565 1.3 0.964 1.4 0.101 2.1 0.065 2.20.359 2.3 0.547 2.4 0.208 2.5 0.535 2.6 0.320 2.7 0.455 2.8 0.245 2.90.300 2.10 0.115 2.11 0.115 2.12 0.090 2.13 0.085 2.14 0.063 2.15 0.0702.16 0.045 2.17 0.118 2.18 0.130 2.19 0.039 2.20 0.053 2.21 0.087 2.220.048 2.23 0.144 2.24 0.133 2.25 0.077 2.26 0.096 2.27 0.103 2.28 0.1922.29 0.204 2.30 0.528 2.31 0.898 2.32 0.809 2.33 0.908 3.1 0.040 3.20.227 3.3 0.445 3.4 1.040 3.5 0.299 3.6 0.605 3.7 0.374 3.8 0.260 3.90.117 3.10 0.045 3.11 0.110 3.12 0.203 3.13 0.050 3.14 0.120 3.15 0.2783.16 0.104 3.17 0.242 3.18 0.113 3.19 0.155 3.20 0.576 4.1 0.065 4.20.244 4.3 0.494 4.4 0.075 4.5 0.085 4.6 0.222 5.1 0.059 5.2 0.049 5.30.065 6.1 0.110 6.2 2.182 6.3 1.029 6.4 1.909 6.5 1.010 6.6 0.830 6.71.078 6.8 0.163 6.9 0.654 6.10 0.929 6.11 0.244 6.12 0.828 6.13 0.5106.14 0.290 6.15 0.220 6.16 0.153 6.17 2.364 6.18 0.935 6.19 0.449 6.200.974 6.21 0.303 6.22 1.349 6.23 1.730 6.24 0.819 6.25 0.714 6.26 0.1207.1 0.035 7.2 0.649 7.3 0.375 7.4 0.373 7.5 0.842 7.6 1.099 7.7 0.8847.8 2.093 7.9 0.879 7.10 0.873 7.11 0.368 7.12 0.585 7.13 0.410 7.140.780 7.15 0.828 7.16 0.405 7.17 0.960 7.18 0.565 7.19 0.065 7.20 0.0357.21 0.045 7.22 0.140 7.23 0.120 7.24 0.394 7.25 0.067 7.26 0.148 7.270.035 7.28 0.069 7.29 0.175 7.30 0.153 7.31 0.049 7.32 0.145 7.33 0.0867.34 0.063 7.35 0.125 7.36 2.900 7.37 0.250 7.38 0.196 7.39 0.060 7.400.042 7.41 0.039 7.42 0.081 7.43 0.452 7.44 0.277 7.45 0.099 7.46 0.5957.47 0.058 7.48 0.087 7.49 0.117 7.50 0.097 7.51 0.392 7.52 0.105 7.530.032 7.54 0.162 7.55 0.069 7.56 0.075 7.57 0.109 7.58 0.355 7.59 0.0397.60 0.145 7.61 0.233 7.62 0.038 7.63 0.112 7.64 0.128 7.65 0.650 7.660.723 7.67 0.789 8.1 0.055 8.2 0.424 8.3 0.125 8.4 1.029 8.5 0.403 8.60.102 8.7 0.865 8.8 0.045 8.9 0.033 8.10 0.190 8.11 0.058 8.12 0.0678.13 0.030 8.14 0.710 8.15 0.410 8.16 0.354 8.17 0.167 8.18 0.160 8.190.475 8.20 0.170 8.21 0.190 8.22 0.986 8.23 0.185 8.24 0.174 8.25 0.2948.26 0.069 8.27 0.065 8.28 0.809 8.29 0.150 8.30 0.184 8.31 0.095 8.321.070 8.33 1.062 8.34 1.085 8.35 0.824 8.36 0.539 8.37 0.349 8.38 1.2188.39 0.452 8.40 0.628 8.41 0.286 8.42 0.632 8.43 0.079 8.44 0.055 8.450.192 8.46 0.089 8.47 0.065 8.48 0.312 8.49 0.219 8.50 0.157 8.51 0.1248.52 0.905 8.53 0.452 8.54 0.125 8.55 0.987 8.56 0.060 8.57 1.002 8.580.484 8.59 0.425 8.60 0.059 8.61 0.245 8.62 0.184 8.63 0.071 8.64 0.7458.65 0.080 8.66 0.065 8.67 0.130 8.68 0.050 8.69 0.102 8.70 0.059 8.710.199 8.72 0.167 8.73 1.044 8.74 0.115 8.75 0.358 8.76 0.155 8.77 0.4898.78 0.260 8.79 0.037 8.80 0.955 8.81 0.970 8.82 0.180 8.83 0.165 8.840.212 8.85 0.566 8.86 0.670 8.87 0.128 8.88 0.130 8.89 0.293 8.90 0.3648.91 0.105 8.92 0.100 8.93 0.440 8.94 0.165 8.95 0.079 8.96 0.265 8.970.079 8.98 0.212 8.99 0.120 8.100 0.180 8.101 0.376 8.102 0.088 8.1030.120 8.104 0.059 8.105 0.251 8.106 0.160 8.107 0.522 8.108 0.375 8.1090.245 8.110 0.234 8.111 0.116 8.112 0.053 8.113 0.040 8.114 0.080 8.1150.166 8.116 0.470 8.117 0.485 8.118 2.463 8.119 0.209 8.120 0.413 8.1210.169 8.122 0.547 8.123 0.920 8.124 0.111 8.125 0.090 8.126 0.058 8.1270.107 8.128 0.278 8.129 0.067 8.130 0.079 8.131 0.461 8.132 0.206 8.1330.299 8.134 0.208 8.135 0.131 8.136 0.070 8.137 0.672 8.138 0.105 8.1390.049 8.140 0.109 8.141 0.148 8.142 0.138 8.143 0.429 8.144 0.104 8.1450.093 8.146 0.984 8.147 2.325 8.148 0.198 8.149 0.387 8.150 0.159 8.1510.273 8.152 0.215 8.153 0.679 8.154 0.103 8.155 0.613 8.156 0.153 8.1570.105 8.158 0.056 8.159 0.151 8.160 0.407 8.161 0.384 8.162 0.476 8.1630.469 8.164 0.102 8.165 0.075 8.166 0.105 8.167 0.101 8.168 0.173 8.1690.277 8.170 0.260 8.171 0.175 8.172 0.675 8.173 0.155 8.174 0.170 8.1751.375 8.176 0.683 8.177 0.476 8.178 0.389 8.179 0.358 8.180 0.278 8.1810.531 8.182 1.115 8.183 0.807 8.184 0.220 8.185 0.753 8.186 0.204 8.1870.220 8.188 0.118 8.189 0.319 8.190 0.041 8.191 0.222 8.192 0.640 8.1930.229 8.194 0.128 8.195 0.393 8.196 0.277 8.197 0.733 8.198 0.549 8.1990.085 8.200 0.354 8.201 0.294 8.202 0.721 8.203 0.334 8.204 0.945 8.2050.607 8.206 0.075 8.207 0.099 8.208 0.172 8.209 0.351 8.210 0.714 8.2110.506 8.212 0.998 8.213 0.360 8.214 0.865 8.215 0.719 8.216 0.125 8.2170.145 8.218 0.140 8.219 0.355 8.220 0.182 8.221 0.269 8.222 0.150 8.2230.103 8.224 0.170 8.225 0.199 8.226 0.052 8.227 0.418 8.228 0.619 8.2290.641 8.230 0.485 8.231 0.127 8.232 0.060 8.233 0.153 8.234 0.898 8.2350.045 8.236 0.314 8.237 0.749 8.238 0.534 8.239 0.487 8.240 0.215 8.2410.594 8.242 0.459 8.243 0.559 8.244 0.165 8.245 0.937 8.246 0.680 8.2470.110 8.248 1.035 8.249 0.404 8.250 0.358 8.251 0.097 8.252 1.061 8.2530.079 8.254 0.060 8.255 0.303 8.256 0.303 8.257 0.121 8.258 0.105 8.2590.173 8.260 0.180 8.261 0.096 8.262 0.129 8.263 0.698 8.264 0.282 8.2650.379 8.266 0.995 8.267 0.064 8.268 0.198 8.269 0.188 8.270 0.455 8.2710.170 8.272 1.189 8.273 1.352 8.274 0.130 8.275 0.183 8.276 0.174 8.2770.867 8.278 0.673 8.279 0.369 8.280 1.230 8.281 0.372 8.282 0.157 8.2830.057 8.284 0.240 8.285 0.089 8.286 0.165 8.287 0.455 8.288 0.874 8.2890.484 8.290 0.765 8.291 0.111 8.292 0.359 8.293 0.050 8.294 0.052 8.2950.790 8.296 0.113 8.297 0.224 8.298 0.156 8.299 0.070 8.300 0.537 8.3010.809 8.302 0.202 8.303 0.301 8.304 0.510 8.305 0.176 8.306 0.181 8.3070.094 8.308 0.105 8.309 0.042 8.310 0.052 8.311 0.062 8.312 0.286 8.3130.306 8.314 0.345 8.315 0.552 8.316 0.580 8.317 0.700 8.318 0.703 8.3190.960 8.320 0.742 8.321 0.830 9.1 0.725 9.2 0.987 9.3 0.342 9.4 0.4649.5 1.009 10.1 0.235 10.2 0.174 10.3 0.406 10.4 0.120 10.5 0.295

In view of their ability to inhibit acetyl-CoA carboxylase(s), thecompounds of general formula (I) according to the invention and thecorresponding salts thereof are theoretically suitable for thetreatment, including preventative treatment of all those diseases orconditions which may be affected or which are mediated by the inhibitionof acetyl-CoA carboxylase(s), in particular ACC2, activity.

Accordingly, the present invention relates to a compound of generalformula (I) as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula (I) for the treatment and/or prevention of diseases orconditions which are mediated by the inhibition of acetyl-CoAcarboxylase(s), in particular ACC2, in a patient, preferably in a human.

In yet another aspect the present invention relates a method fortreating, including preventing a disease or condition mediated by theinhibition of acetyl-CoA carboxylase(s) in a mammal that includes thestep of administering to a patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention, or a pharmaceutical composition thereof.

Diseases and conditions mediated by inhibitors of acetyl-CoAcarboxylases embrace metabolic and/or cardiovascular and/orneurodegenerative diseases or conditions.

According to one aspect the compounds of the present invention areparticularly suitable for treating diabetes mellitus, in particular Type2 diabetes, Type 1 diabetes, and diabetes-related diseases, such asishyperglycemia, metabolic syndrome, impaired glucose tolerance,diabetic neuropathy, diabetic nephropathy, diabetic retinopathy,dyslipidemia, hypertension, hyperinsulinemia, and insulin resistancesyndrome, hepatic insulin resistance, including complications such asmacro- and microvascular disorders, including thromboses,hypercoagulable and prothrombotic states (arterial and venous), highblood pressure, coronary artery disease and heart failure, increasedabdominal girth, hypercoagulability, hyperuricemia, micro-albuminemia.

According to another aspect the compounds of the present invention areparticularly suitable for treating overweight, obesity, includingvisceral (abdominal) obesity, nonalcoholic fatty liver disease (NAFLD)and obesity related disorders, such as for example weight gain or weightmaintenance.

Obesity and overweight are generally defined by body mass index (BMI),which is correlated with total body fat and estimates the relative riskof disease. BMI is calculated by weight in kilograms divided by heightin meters squared (kg/m²). Overweight is typically defined as a BMI of25-29.9 kg/m², and obesity is typically defined as a BMI of 30 kg/m² orgreater.

According to another aspect the compounds of the present invention areparticularly suitable for treating, including preventing, or delayingthe progression or onset of diabetes or diabetes-related disordersincluding Type 1 (insulin-dependent diabetes mellitus, also referred toas “IDDM”) and Type 2 (noninsulin-dependent diabetes mellitus, alsoreferred to as “NIDDM”) diabetes, impaired glucose tolerance, insulinresistance, hyperglycemia, pancreatic beta cell degeneration anddiabetic complications (such as macro- and microvascular disorders,atherosclerosis, coronary heart disease, stroke, peripheral vasculardisease, nephropathy, hypertension, neuropathy, and retinopathy).

In addition the compounds of the present invention are suitable fortreating dyslipidemias in general and more specifically elevated lipidconcentrations in the blood and in tissues, dysregulation of LDL, HDLand VLDL, in particular high plasma triglyceride concentrations, highpostprandial plasma triglyceride concentrations, low HDL cholesterolconcentration, low apoA lipoprotein concentrations, high LDL cholesterolconcentrations, high apoB lipoprotein concentrations, includingatherosclerosis, coronary heart disease, cerebrovascular disorders,diabetes mellitus, metabolic syndrome, obesity, insulin resistanceand/or cardiovascular disorders.

ACC inhibition may lead to a centrally stimulating effect on foodintake. Therefore compounds of the present invention may be suitable fortreating eating disorders such as anorexia nervosa.

In addition the compounds of the present invention may provideneuroprotective effects in patients with Parkinson's disease,Alzheimer's disease, hypoxia, ischemia, amyotrophic lateral sclerosis orglioma and may improve cognitive scores in Alzheimer's diseasespatients.

Further diseases and conditions mediated by inhibitors of acetyl-CoAcarboxylases embrace but are not limited to:

-   A. disorders of fatty acid metabolism and glucose utilization    disorders; disorders in which insulin resistance is involved;-   B. hepatic disorders and conditions related thereto, including:    -   fatty liver, hepatic steatosis, non-alcoholic hepatitis,        non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, acute        fatty liver, fatty liver of pregnancy, drug-induced hepatitis,        iron storage diseases, hepatic fibrosis, hepatic cirrhosis,        hepatoma, viral hepatitis;-   C. skin disorders and conditions and those associated with    polyunsaturated fatty acids, such as    -   eczema, acne, sebaceous gland diseases, psoriasis, keloid scar        formation or prevention, other diseases related to mucous        membrane fatty acid composition;-   D. primary hypertriglyceridemia or secondary hypertriglyceridemias    following familial histiocytic reticulosis, lipoprotein lipase    deficiency, hyperlipoproteinemias, apolipoprotein deficiency (e.g.    apoCII or apoE deficiency);-   E. diseases or conditions related to neoplastic cellular    proliferation, for example benign or malignant tumors, cancer,    neoplasias, metastases, carcinogenesis;-   F. diseases or conditions related to neurological, psychiatric or    immune disorders or conditions;-   G. other diseases or conditions in which inflammatory reactions,    cell differentiation and/or other ACC-mediated aspects may for    example be involved are:    -   atherosclerosis such as, for example (but not restricted        thereto), coronary sclerosis including angina pectoris or        myocardial infarction, stroke, ischemic, stroke and transient        ischemic attack (TIA),    -   peripheral occlusive disease,    -   vascular restenosis or reocclusion,    -   chronic inflammatory bowel diseases such as, for example,        Crohn's disease and ulcerative colitis,    -   pancreatitis,    -   sinusitis,    -   retinopathy, ischemic retinopathy,    -   adipose cell tumors,    -   lipomatous carcinomas such as, for example, liposarcomas,    -   solid tumors and neoplasms such as, for example (but not        restricted thereto), carcinomas of the gastrointestinal tract,        of the liver, of the biliary tract and of the pancreas,        endocrine tumors, carcinomas of the lungs, of the kidneys and        the urinary tract, of the genital tract, prostate carcinomas,        breast cancer (in particular breast cancer with BRCA1        mutations), etc.,    -   tumors in which ACC is up regulated,    -   acute and chronic myeloproliferative disorders and lymphomas,        angiogenesis    -   neurodegenerative disorders including Alzheimer's disease,        multiple sclerosis, Parkinson's disease, epilepsy,    -   erythemato-squamous dermatoses such as, for example, psoriasis,    -   acne vulgaris,    -   other skin disorders and dermatological conditions which are        modulated by PPAR,    -   eczemas and neurodermatitis,    -   dermatitis such as, for example, seborrheic dermatitis or        photodermatitis,    -   keratitis and keratoses such as, for example, seborrheic        keratoses, senile keratoses, actinic keratoses, photo-induced        keratoses or keratosis follicularis,    -   keloids and keloid prophylaxis,    -   bacterial infections,    -   fungal infections,    -   warts, including condylomata or condylomata acuminata    -   viral infections such as, for example, human hepatitis B virus        (HBV), hepatitis C virus (HCV), West Nile virus (WNV) or Dengue        virus, human Immunodeficiency virus (HIV), poxvirus and Vaccinia        virus (VV), HCMV, influenza A, human papilloma viral (HPV).        venereal papillomata, viral warts such as, for example,        molluscum contagiosum, leukoplakia,    -   papular dermatoses such as, for example, lichen planus,    -   skin cancer such as, for example, basal-cell carcinomas,        melanomas or cutaneous T-cell lymphomas,    -   localized benign epidermal tumors such as, for example,        keratoderma, epidermal naevi,    -   chilblains;    -   high blood pressure,    -   polycystic ovary syndrome (PCOS),    -   asthma,    -   cystic fibrosis,    -   osteoarthritis,    -   lupus erythematosus (LE) or inflammatory rheumatic disorders        such as, for example rheumatoid arthritis,    -   vasculitis,    -   wasting (cachexia),    -   gout,    -   ischemia/reperfusion syndrome,    -   acute respiratory distress syndrome (ARDS)    -   viral diseases and infections    -   lipodystrophy and lipodystrophic conditions, also for treating        adverse drug effect;    -   myophathies and lipid myopathis (such as carnitine        palmitoyltransferase I or II deficiency);-   H. formation of muscles and a lean body or muscle mass formation.

The dose range of the compounds of general formula (I) applicable perday is usually from 0.001 to 10 mg per kg body weight of the patient,preferably from 0.01 to 8 mg per kg body weight of the patient. Eachdosage unit may conveniently contain 0.1 to 1000 mg of the activesubstance, preferably it contains between 0.5 to 500 mg of the activesubstance.

The actual therapeutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the combination will be administered at dosages andin a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula (I)will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. The content of the pharmaceutically active compound(s) isadvantageously in the range from 0.1 to 90 wt.-%, for example from 1 to70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula (I) with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsassociated with metabolic diseases or conditions such as for examplediabetes mellitus, obesity, diabetic complications, hypertension,hyperlipidemia.

Therefore a compound of the invention may be combined with one or moreadditional therapeutic agents selected from the group consisting ofanti-obesity agents (including appetite suppressants), agents whichlower blood glucose, anti-diabetic agents, agents for treatingdyslipidemias, such as lipid lowering agents, anti-hypertensive agents,antiatherosclerotic agents, anti-inflammatory active ingredients, agentsfor the treatment of malignant tumors, antithrombotic agents, agents forthe treatment of heart failure and agents for the treatment ofcomplications caused by diabetes or associated with diabetes.

Suitable anti-obesity agents include 11beta-hydroxy steroiddehydrogenase-1 (11beta-HSD type 1) inhibitors, stearoyl-CoAdesaturase-1 (SCD-1) inhibitors, MCR-4 agonists, cholecystokinin-A(CCK-A) agonists, monoamine reuptake inhibitors, sympathomimetic agents,beta3 adrenergic agonists, dopamine agonists, melanocyte-stimulatinghormone analogs, 5HT2c agonists, melanin concentrating hormoneantagonists, leptin (the OB protein), leptin analogs, leptin agonists,galanin antagonists, lipase inhibitors, anorectic agents, neuropeptide-γantagonists (e.g., NPY Y5 antagonists), PY_(Y3-36) (including analogsthereof), thyromimetic agents, dehydroepiandrosterone or an analogthereof, glucocorticoid agonists or antagonists, orexin antagonists,glucagon-like peptide-1 agonists, ciliary neurotrophic factors, humanagouti-related protein (AGRP) inhibitors, ghrelin antagonists, GOAT(Ghrelin O-Acyltransferase) inhibitors, histamine 3 antagonists orinverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g.,gut-selective MTP inhibitors), opioid antagonists, orexin antagonists,and the like.

Preferred anti-obesity agents for use in the combination aspects of thepresent invention include gut-selective MTP inhibitors CCKa agonists,5HT2c agonists, MCR4 agonists, lipase inhibitors, opioid antagonists,oleoyl-estrone, obinepitide, pramlintide (Symlin®), tesofensine(NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide(Byetta®), AOD-9604 (CAS No. 221231-10-3) and sibutramine.

Suitable anti-diabetic agents include sodium-glucose co-transporter(SGLT) inhibitors, 11beta-hydroxy steroid dehydrogenase-1 (11beta-HSDtype 1) inhibitors, phosphodiesterase (PDE) 10 inhibitors,diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, sulfonylureas(e.g., acetohexamide, chiorpropamide, diabinese, glibenclamide,glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone,glisolamide, tolazamide, and tolbutamide), meglitinides, analpha-amylase inhibitors (e.g., tendamistat, trestatin and AL-3688),alpha-glucoside hydrolase inhibitors (e.g., acarbose), alpha-glucosidaseinhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol,voglibose, pradimicin-Q, and salbostatin), PPAR gamma agonists (e.g.,balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone,pioglitazone, rosiglitazone and troglitazone), PPAR alpha/gamma agonists(e.g., CLX-0940, GW-1536, GW-20 1929, GW-2433, KRP-297, L-796449, LR-90,MK-0767 and SB-219994), biguanides (e.g., metformin), GLP-1 derivatives,glucagon-like peptide 1 (GLP-1) agonists (e.g., Byetta™, exendin-3 andexendin-4), GLP-1 receptor and glucagon receptor co-agonists, glucagonreceptor antagonists, GIP receptor antagonists, protein tyrosinephosphatase-1 B (PTP-1 B) inhibitors (e.g., trodusquemine, hyrtiosalextract), SIRT-1 activators (e.g. reservatrol), dipeptidyl peptidease IV(DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin,linagliptin and saxagliptin), insulin secretagogues, GPR119 agonists,GPR40 agonists, TGR5 agonists, MNK2 inhibitors, GOAT (GhrelinO-Acyltransferase) inhibitors, fatty acid oxidation inhibitors, A2antagonists, c-jun amino-terminal kinase (JNK) inhibitors, insulins,insulin derivatives, fast acting insulins, inhalable insulins, oralinsulins, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2receptor agonists and glucokinase activators.

Preferred anti-diabetic agents are metformin, glucagon-like peptide 1(GLP-1) agonists (e.g., Byetta™), GLP-1 receptor and glucagon receptorco-agonists, sodium-glucose co-transporter (SGLT) inhibitors,11beta-hydroxy steroid dehydrogenase-1 (11beta-HSD type 1) inhibitorsand DPP-IV inhibitors (e.g. sitagliptin, vildagliptin, alogliptin,linagliptin and saxagliptin).

Preferably, compounds of the present invention and/or pharmaceuticalcompositions comprising a compound of the present invention optionallyin combination with one or more additional therapeutic agents areadministered in conjunction with exercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention in combination with one or moreadditional therapeutic agents described hereinbefore and hereinafter forthe treatment or prevention of diseases or conditions which may beaffected or which are mediated by the inhibition of the acetyl-CoAcarboxylase(s), in particular ACC2, in particular diseases or conditionsas described hereinbefore and hereinafter.

In yet another aspect the present invention relates a method fortreating, including preventing a disease or condition mediated by theinhibition of acetyl-CoA carboxylase(s) in a patient that includes thestep of administering to the patient, preferably a human, in need ofsuch treatment a therapeutically effective amount of a compound of thepresent invention in combination with a therapeutically effective amountof one or more additional therapeutic agents described in hereinbeforeand hereinafter,

The use of the compound according to the invention in combination withthe additional therapeutic agent may take place simultaneously or atstaggered times.

The compound according to the invention and the one or more additionaltherapeutic agents may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention and one or more additional therapeutic agents describedhereinbefore and hereinafter, optionally together with one or more inertcarriers and/or diluents.

Further aspects of the invention include the use of a compound accordingto the invention or a salt thereof as a crop protection agent to combatand/or prevent fungal infestations, or to control other pests such asweeds, insects, or acarids that are harmful to crops. Another aspect ofthe invention relates to the use of a compound according to theinvention or a salt thereof for controlling and/or preventing plantpathogenic microorganisms, for example plant pathogenic fungi. Thereforeone aspect of the invention is a compound according to the formula (I)or a salt thereof for use as a fungicide, insecticide, acaricide and/orherbicide. Another aspect of the invention relates to an agriculturalcomposition comprising a compound of the present invention together withone or more suitable carriers. Another aspect of the invention relatesto an agricultural composition comprising a compound of the presentinvention in combination with at least one additional fungicide and/orsystemically acquired resistance inducer together with one or moresuitable carriers.

Synthesis Schemes

Compounds of general formula (I) may be prepared by palladium-mediatedBuchwald reactions or copper-mediated Ullmann reactions of pyrimidines(Py; II), that are substituted with 1-3 R¹, with pyrrolidines (III)wherein Z is a leaving group and for example denotes Cl, Br or I.

Compounds of general formula (I) may be prepared by amide couplingreactions of amines (IV) with carboxylic acids (V) mediated by couplingreagents such as for example2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborat(TBTU), 1-chloro-N,N-2-trimethylpropenylamine,benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate and2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate.

Alternatively, compounds of general formula (I) may be prepared by amidecoupling reactions of amines (IV) with carboxylic acids chlorides (VI)or carboxylic acid anhydrides (VII).

Compounds of general formula (VIII) may be prepared by alkylationreactions of aromatic alcohols (IX) with electrophiles (X) wherein Z isa leaving group which for example denotes Cl, Br, I, mesylate, tosylateor triflate and R^(HetAryl) is heteroaryl such as for example pyridinyl.

Compounds of general formula (XI) may be prepared by urea formingreactions such as reaction of amines (IV) with amines (XII) afterreaction with reagents such as N,N-carbonylditriazole (CDT) orN,N-carbonyldiimidazole (CDI).

Compounds of general formula (XIII) may be prepared by urethane formingreactions such as reaction of amines (IV) with alcohols (XIV), whereinR⁸ is (C₁₋₄-alkyl) which is optionally substituted with C₃₋₇-cycloalkyl,after reaction with reagents such as CDT or CDI. Alcohols may be used intheir deprotonated form.

Alternatively, compounds of general formula (XIII) may be prepared byurethane forming reactions such as reaction of amines (IV) with chloroformates (XV).

Compounds of general formula (I) may alternatively be prepared bynucleophilic aromatic substitution reactions (S_(N)Ar) of pyrimidylhalides (XVI) with pyrrolidines (III), wherein Z is a leaving groupwhich for example denotes F, Cl, Br, I.

Compounds of general formula (XVII) may be prepared by aromaticsubtitution of pyrimidyl halides (XVIII) with amines (XII) wherein Z isa leaving group which for example denotes F or Cl, Br, I.

Compounds of general formula (XIX) may be prepared by aromaticsubstitution of pyrimidyl halides (XVIII) with alcohols (XIV) wherein Zis a leaving group which for example denotes F or Cl, Br, I. Alcoholsare used in their deprotonated form.

Compounds of general formula (XX) wherein Ar is aryl may be prepared bypalladium-mediated Suzuki reactions of pyrimidine halides (XVIII) withboronic acids (XXI) or corresponding boronic esters wherein Z is aleaving group which for example denotes Cl, Br or I.

Compounds of general formula (XXII) may be prepared by acetylations suchas reaction of amines (XXIII) with carboxylic acids chlorides (VI).

Experimental Part

The Examples that follow are intended to illustrate the presentinvention without restricting it. The terms “ambient temperature” and“room temperature” are used interchangeably and designate a temperatureof about 20° C.

Preliminary Remarks:

As a rule, 1H-NMR and/or mass spectra have been obtained for thecompounds prepared. The R_(f) values are determined using silica gelplates and UV light at 254 nm.

To describe the relative configuration of stereogenic centers straightbars are used. To describe the relative and absolute configuration, thebars have a wedged shape.

realtiv configuration:

relative and absolute configuration:

Experimental Part

Abreviations: aq. aqueous ACN acetonitrile AcOH acetic acid BOCtert-butoxy-Carbonyl- BuLi butyl lithium CDI N,N-carbonyldiimidazole CDTN,N-carbonylditriazole CIP 2-chloro-1,3-dimethyl-2-imidazoliniumhexafluorophosphate CyH cyclohexane d day DCM dichloromethane DIPEdiisopropyl ether DIPEA N,N-diisopropylethylamine DMAP4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide dppf diphenylphosphinoferrocene EtOAc ethyl acetate EtOHethanol eq equivalent Ex example FA formic acid h hour MeOH methanol minminute MsCl methanesulfonyl chloride n.d. not determined NMPN-methyl-2-pyrrolidone Pd/C palladium on activated carbon PE petroleumether PyBop (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate r.t. room temperature (about 20° C.) sat. saturatedTBME tert-butyl methyl ether TEA triethylamine TF/TFA trifluoroaceticacid THF tetrahydrofuran TBAF tetrabutylammonium fluoride TBTU2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborat TMStrimethylsilyl Ts 4-toluenesulfonyl THP tetrahydropyran X-Phos2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl

Preparation of Starting Compounds Example I(S)—N-(1-(4-Bromophenyl)ethyl)acetamide

To 200 g (1.00 mol) (S)-1-(4-bromophenyl)ethylamine in 800 mL DCM areslowly added 94.5 mL (1.00 mol) acetic anhydride while cooling themixture to 20-30° C. Then the cooling is removed and the reactionmixture is stirred at r.t. over night. Afterwards the mixture isconsecutively washed with water, sat. aq. NaHCO₃ solution, water,diluted aq. citric acid solution and again water. The org. layer isdried over MgSO₄, filtered and the solvent is removed in vacuo. Thecrude product is used without further purification.

C₁₀H₁₂BrNO (M=242.1 g/mol)

ESI-MS: 242/244 [M+H]⁺

R_(t) (HPLC): 1.67 min (method A)

Example II (S)-tert-Butyl 1-(4-bromophenyl)ethylcarbamate

To 150 g (735 mmol) (S)-1-(4-bromophenyl)ethylamine in 2 L DCM are added459 mL (918 mmol) of an aq. Na₂CO₃ solution (c=2 mol/L). To this mixturea solution of 164 g (749 mmol) BOC₂O in 350 mL THF is added dropwise atr.t. and stirring is continued for 1 h. Then the mixture is poured ontowater and stirred for additional 20 min. The layers are separated, theorg. layer is washed with water (2×), dried over Na₂SO₄, filtered andthe solvent is removed in vacuo.

C₁₃H₁₈BrNO₂ (M=300.2 g/mol)

ESI-MS: 300/302 [M+H]⁺

R_(t) (TLC): 0.90 (silica gel, DCM/MeOH 9/1)

Example III Example III.1 (General Route)(S)—N-(1-(4-Hydroxyphenyl)ethyl)acetamide

a) To a mixture of 60.0 g (248 mmol) of example I, 73.0 g (743 mmol)KOAc, 94.4 g (372 mmol) bis(pinakolato)diboron and 3.62 g (4.96 mmol)PdCl₂(dppf) in an atmosphere of argon are added 450 mL DMSO and theresulting mixture is degassed twice and stirred at 80° C. for 3 h. Thenthe reaction mixture is cooled down to r.t., diluted with water andEtOAc and the layers are separated. The aq. layer is extracted withEtOAc (2×). The org. layers are combined, washed with water (3×), driedover MgSO₄, filtered through a plug of Celite® and the solvent isremoved in vacuo. The crude product is used without furtherpurification.

C₁₆H₂₄BrNO₃ (M=289.2 g/mol)

ESI-MS: 290 [M+H]⁺

R_(t) (HPLC): 1.19 min (method B)

b) 80.0 g (180 mmol) of the above mentioned product are added to 500 mLTHF and cooled down to 0° C. 31.8 mL (360 mmol) H₂O₂ (35% in water) andsubsequently 51.7 mL (155 mmol) 4N aq. NaOH solution and are added andthe resulting mixture is stirred for 2 h at constant temperature. EtOAcis added and the mixture is extracted with 1N aq. NaOH solution (2×).The org. layer is washed with EtOAc, acidified with citric acid andextracted with EtOAc (3×). The org. layers are combined, washed with aNa₂S₂O₃ solution (10% in water), dried over Na₂SO₄, filtered and thesolvent is removed in vacuo. The resulting product is triturated withTBME.

C₁₀H₁₃NO₂ (M=179.2 g/mol)

ESI-MS: 180 [M+H]⁺

R_(t) (HPLC): 0.30 min (method C)

The following compounds are prepared analogously to example III.1

HPLC Mass spec retention time Ex. Starting material Product structureresult (method) III.1

180 [M + H]⁺ 0.30 (C) III.2

238 [M + H]⁺ 1.58 (A)

Example IV (S)-benzyl 1-(4-hydroxyphenyl)ethylcarbamate

a) 10.0 g (66.1 mmol) (S)-4-methoxy-alpha-methylbenzylamine are added to30 mL HBr (30% in AcOH) and stirred at 100° C. for 4 h. The reactionmixture is cooled to r.t. and the acid is removed in vacuo. The crudeproduct is used without further purification.

b) 5.00 g (22.9 mmol) of the above mentioned product are added to 10 mLTHF and 10 mL H₂O before 13.5 g (160 mmol) NaHCO₃ are added. Then 3.60mL (25.2 mmol) benzyl chloroformate are added dropwise and the reactionmixture is stirred at r.t. for 3 h. Afterwards the reaction mixture isquenched by the addition of water and is set to a gentle acidic pH valuewith citric acid (10% in water). Then the product is extracted withEtOAc, the combined organic layers are dried over MgSO₄, filtered andthe solvent is removed in vacuo. The crude product is purified by flashchromatography (silica gel, PE/EtOAc).

C₁₆H₁₇NO₃ (M=271.3 g/mol)

ESI-MS: 272 [M+H]⁺

R_(t) (HPLC): 1.65 min (method A)

Example V (R)-tert-Butyl3-(4-((S)-1-(benzyloxycarbonylamino)ethyl)phenoxy)pyrrolidine-1-carboxylate

6.00 g (22.6 mmol) 3-methanesulfonyloxy-pyrrolidine-1-carboxylic acidtert-butyl ester*, 6.14 g (22.6 mmol) of example IV and 14.7 g (45.2mmol) Cs₂CO₃ are added to 80 mL DMF and stirred at 80° C. over night.The reaction mixture is filtered, washed with MeOH and the solvent isremoved in vacuo. The crude product is purified by HPLC (MeOH/H₂O/NH₃).

C₂₅H₃₂N₂O₅ (M=440.5 g/mol)

ESI-MS: 439 [M−H]⁻

R_(t) (HPLC): 1.22 min (method C) *A representative procedure for thepreparation of N-protected 3-methylsulfonyloxypyrrolidines can be foundin Zersh et al. Synthesis 2011, 22, 3669-3674

Example VI Example VI.1 (General Route) (R)-tertButyl-3-(4-((S)-1-acetamidoethyl)phenoxy)pyrrolidine-1-carboxylate

20.0 g (75.4 mmol) (S)-tert butyl3-(methylsulfonyloxy)-pyrrolidine-1-carboxylate*, 13.5 g (75.4 mmol) ofexample III.1 and 49.1 g (151 mmol) Cs₂CO₃ are added to 150 mL DMF andstirred for 16 h at 80° C. Then the reaction mixture is cooled down tor.t., diluted with water and extracted with EtOAc (2×). The org. layersare combined, washed with aq. NaHCO₃ solution (3×) and dried over MgSO₄.After filtration the solvent is removed in vacuo and the crude productis purified by flash chromatography (silica gel, DCM/MeOH 93/7).

C₁₉H₂₈N₂O₄ (M=348.4 g/mol)

ESI-MS: 349 [M+H]⁺

R_(t) (HPLC): 1.02 min (method C)

The following compounds are prepared analogously to example VI.1

HPLC Mass retention spec time Ex. Starting material(s) Product structureresult (method) VI.1 III.1 + (S)-tert Butyl 3- (methylsulfonyloxy)-pyrrolidine-1-carboxylate*

349 [M + H]⁺ 1.02 (C) VI.2 III.1 + (R)-tert Butyl 3-(methylsulfonyloxy)- pyrrolidine-1-carboxylate*

349 [M + H]⁺ 2.15 (A) VI.3 III.2 + (S)-Benzyl 3- (methylsulfonyloxy)-pyrrolidine-1-carboxylate*

441 [M + H]⁺ 1.22 (C) *A representative procedure for the preparation ofN-protected 3-methylsulfonyloxy-pyrrolidines can be found in Zersh etal. Synthesis 2011, 22, 3669-3674;

Example VII Example VII.1 (General Route)N—((S)-1-(4-((R)-pyrrolidin-3-yloxy)phenyl)ethyl)acetamide hydrochloride

To 20.5 g (58.8 mmol) of example VI.1 in 200 mL dioxane are added 29.4mL (118 mmol) HCl in dioxane (c=4 mol/L) and the resulting mixture isstirred at r.t. over night. Additional 15 mL (60 mmol) HCl in dioxane(c=4 mol/L) are added and stirring is continued for 1 d. Then thereaction mixture is treated with TBME and the precipitate is filtered,washed with TBME and dried at 40° C. in vacuo.

C₁₄H₂₀N₂O₂*HCl (M=284.8 g/mol)

ESI-MS: 249 [M+H]⁺

R_(t) (HPLC): 0.63 min (method C)

The following compounds are prepared analogously to example VII.1

For the examples VII.3 and VII.4 the resulting product is transferredinto the free base using a NaOH solution (c=1 mol/L).

HPLC Mass retention spec time Ex. Starting material Product structureresult (method) VII.1 VI.1

249 [M + H]⁺ 0.63 (C) VII.2 VI.2

249 [M + H]⁺ 1.30 (A) VII.3 VI.1

249 [M + H]⁺ 0.54 (B) VII.4 VI.2

249 [M + H]⁺ 1.30 (A) VII.5 V

341 [M + H]⁺ 1.00 (C)

Example VIII (R)-Benzyl3-(4-((S)-1-aminoethyl)phenoxy)pyrrolidine-1-carboxylate hydrochloride

4.70 g (10.7 mmol) of example VI.3 in 25 mL dioxane are charged with5.33 mL (21.3 mmol) of a HCl solution in dioxane (c=4 mol/L) and stirredat r.t. over night. The solvent is removed in vacuo and the residue istaken up in ethanol and the solvent is removed again. The resultingproduct is triturated with DIPE and dried at 50° C.

C₂₀H₂₄N₂O₃*HCl (M=376.9 g/mol)

ESI-MS: 324 [M+H−NH₃]⁺

R_(t) (HPLC): 1.07 min (method C)

Example IX Example IX.1 (General Route) (R)-Benzyl3-(4-((S)-1-(thiazole-5-carboxamido)ethyl)phenoxy)pyrrolidine-1-carboxylate

3.80 g (10.1 mmol) of example VIII in 20 mL DMF are charged with 5.15 mL(29.9 mmol) DIPEA, 3.80 g (11.5 mmol) TBTU and finally after 10 min with1.29 g (9.99 mmol) thiazole-5-carboxylic acid. The reaction mixture isstirred at r.t. over night. The next day water is added and the mixtureis extracted with EtOAc (3×). The organic layers are combined, driedover MgSO₄, filtered and the solvent is removed in vacuo. The crudeproduct is purified by flash chromatography (silica gel, EtOAc). Thenthe product is added to EtOAc and washed with a saturated aq. NaHCO₃solution (3×), dried over MgSO₄, filtered and the solvent is removed invacuo.

C₂₄H₂₅N₃O₄S (M=451.5 g/mol)

ESI-MS: 452 [M+H]⁺

R_(t) (HPLC): 0.92 min (method D)

The following compounds are prepared analogously to example IX.1

For the examples IX.2 the reaction is stirred for 4 h and a preciptateis formed. The solvent is reduced in vacuo and the residue suspended inwater, filtered, washed with tert-butyl methylether and dried at 40° C.in an oven with recirculating air.

HPLC Mass retention spec time Ex. Starting material Product structureresult (method) IX.2 VIII + XXIII

537 [M + H]⁺ 0.72 (D)

Example X tert-Butyl(S)-1-(4-((R)-pyrrolidin-3-yloxy)phenyl)ethyl)carbamate

15.0 g (34.1 mmol) of example VI.3 in 200 mL methanol are hydrogenatedat r.t. using 1.50 g Pd/C (10%) and a hydrogen pressure of 3 bar. Aftercompletion the reaction mixture is filtered and the solvent is removedin vacuo.

C₁₇H₂₆N₂O₃ (M=306.4 g/mol)

ESI-MS: 307 [M+H]⁺

R_(t) (HPLC): 1.01 min (method C)

Example XI Example XI.1 (General Route)N—((S)-1-(4-((R)-pyrrolidin-3-yloxy)phenyl)ethyl)thiazole-5-carboxamide

2.30 g (5.09 mmol) of example IX in 70 mL ACN are charged with 3.68 mL(25.7 mmol) iodotrimethylsilane and stirred at r.t. for 1 h. Thereaction is quenched by the addition of some water. Solvent is removedin vacuo and the crude product is purified by HPLC (ACN/H₂O/FA).

C₁₆H₁₉N₃O₂S (M=317.4 g/mol)

ESI-MS: 318 [M+H]⁺

R_(t) (HPLC): 0.69 min (method D)

The following compounds are prepared analogously to example XI.1

HPLC Mass retention spec time Ex. Starting material Product structureresult (method) XI.2 IX.2

403 [M + H]⁺ 0.72 (D)

Example XII Example XII.1 (General Route)2-Chloro-5-iso-butoxy-pyrimidine

0.80 mg (6.13 mmol) 2-chloro-5-hydroxypyrimidine, 1.26 g (9.19 mmol)1-bromo-2-methylpropane and 1.69 g (12.26 mmol) K₂CO₃ are added to 10 mLDMF and stirred at 80° C. over night. Afterwards the reaction isquenched by the addition of water and extracted with EtOAc. The org.layers are combined, dried over MgSO₄, filtered and the solvent isremoved in vacuo.

C₈H₁₁ClN₂O (M=186.6 g/mol)

ESI-MS: 187 [M+H]⁺

R_(t) (HPLC): 1.04 min (method D)

The following compounds are prepared analogously to example XII.1.

For example XII.4 the reaction conditions are 100° C. for 30 min.

HPLC Mass retention Starting spec time Ex. material Starting materialProduct structure result (method) XII.1

187 [M + H]⁺ 1.04 (D) XII.2

185 [M + H]⁺ 1.23 (J) XII.3

221 [M + H]⁺ 0.91 (I) XII.4

199 [M + H]⁺ 1.06 (D) XII.5

199 [M + H]⁺ 0.86 (H)

Example XIII Example XIII.1 (General Route)4-Chloro-6-cyclopropylmethoxy-5-fluoro-pyrimidine

0.55 mL (5.99 mmol) cyclopropane methanol in 15 mL THF are charged with0.31 g (7.19 mmol) NaH and the reaction mixture is stirred at r.t. for10 min. Then 1.00 g (5.99 mmol) 4,6-dichloro-5-fluoro-pyrimidine areadded and stirred at r.t. for 1 h. Afterwards the reaction is quenchedby the addition of water and extracted with EtOAc. The organic layersare combined, washed with water (2×), dried over MgSO₄, filtered and thesolvent is removed in vacuo.

C₈H₈ClFN₂O (M=202.6 g/mol)

ESI-MS: 203 [M+H]⁺

R_(f) (TLC): 0.37 (silica gel, PE/EtOAc 9/1)

The following compounds are prepared analogously to example XIII.1.

For example XIII.2 KOtBu is used as base and added portionwise at 0° C.to the alcohol. The mixture is added at 0° C. to the correspondingpyrimidine in THF.

HPLC Mass retention spec time Ex. Starting material Product structureresult (method) XIII.2

215 [M + H]⁺ 0.87 (H)

Example XIV 5-tert-Butyl-2-chloro-pyrimidine

a) To 1.00 g (8.19 mmol) tert-butylmalononitroletrade in 6 mL tolueneare added 16 mL (240 mmol) di-iso-butylammoniumhydride (c=1.5 mol/L intoluene) at −60° C. Cooling is removed and the reaction mixture isstirred at r.t. for 4 h. The reaction is quenched by the addition of 1 Naq. HCl and extracted with EtOAc (3×). The org. layers are combined,dried over Na₂SO₄, filtered and the solvent is removed in vacuo. Thecrude product is used without further purification.

C₇H₁₂O₂ (M=128.2 g/mol)

ESI-MS: 129 [M+H]⁺

R_(t) (HPLC): n.d.

b) Under inert gas atmosphere to 1 mL HCl (C=10 mol/L) are added to 225mg (3.75 mmol) urea in 10 mL EtOH and stirred at r.t. for 10 min. Then400 mg (3.12 mmol) of the above mentioned product are added and theresulting mixture is stirred at reflux for 40 h. The reaction isquenched by the addition of water and extracted with DCM. The aq. layeris basified with NaOH to pH 8 and extracted with DCM. Then the combinedorg. layers are dried over Na₂SO₄, filtered and the solvent is removedin vacuo. The crude product is used without further purification.

c) 300 mg (1.97 mmol) of the above mentioned product and 9 mL POCl₃ arestirred at 160° C. for 3 h. The solvent is removed in vacuo and theresidue is treated with water and basified with aq NaOH solution (c=3mol/L) to pH 10. The resulting mixture is extracted with DCM and driedover Na₂SO₄, filtered and the solvent is removed in vacuo. The crudeproduct is purified by flash chromatography (silica gel, DCM/MeOH 98/2).

C₈H₁₁ClN₂ (M=170.6 g/mol)

ESI-MS: 171 [m+H]⁺

Example XV 1-(Tetrahydro-pyran-2-yl)-1H-pyrazole-4-carboxylic acid

a) To 1.00 g (7.14 mmol) ethyl 4-pyrazolecarboxylate and 0.98 mL (10.7mml) 3,4-dihydro-2H-pyran an 20 mL THF are added 0.94 mL (12.1 mmol) TFAand the reaction mixture is stirred at 80° C. over night. Afterwards thereaction mixture is diluted with DCM and charged with aq. NaHCO₃solution. The layers are separated and the org. layer is dried overMgSO₄, filtered and the solvent is removed in vacuo.

C₁₁H₁₆N₂O₃ (M=224.3 g/mol)

ESI-MS: 247 [M+Na]⁺

R_(t) (HPLC): 1.23 min (method M)

b) To 1.67 g (7.45 mmol) of the above mentioned product in 10 mL EtOH11.2 mL (11.2 mmol) NaOH solution (c=1 mol/L) is added and stirred atr.t. for 4 h. Then the organic solvent is removed in vacuo and theresidue is acidified with citric acid (c=1 mol/L) and extracted withEtOAc (2×). The combined org. layers are dried over MgSO₄, filtered andthe solvent is removed in vacuo.

C₉H₁₂N₂O₃ (M=196.2 g/mol)

ESI-MS: 195 [M−H]⁻

R_(t) (HPLC): 0.60 min (method D)

Example XVI Example XVI.1 (General Route)N—((S)-1-(4-((R)-1-(2-chloropyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethyl)acetamide

1.00 g (3.51 mmol) of example VII.1, 0.52 g (3.51 mmol)2,4-dichloropyrimidine and 0.99 mL (7.02 mmol) TEA are added to 10 mLTHF and stirred at 80° C. for 2 h. The reaction mixture is diluted withdiethylether. The precipitate is filtered and dried.

C₁₈H₂₁ClN₄O₂ (M=360.8 g/mol)

ESI-MS: 361 [M+H]⁺

R_(t) (HPLC): 1.06 min (method G)

The following compounds are prepared analogously to example XVI.1

For the examples XVI.2, XVI.3 and XVI.15 the reaction conditions arer.t. over night.

For the examples XVI.4, XVI.7, XVI.9, XVI.10, XVI.11, the reaction timeis over night.

For the examples XVI.5, XVI.6, XVI.12, XVI.13 ACN is used as solvent,K₂CO₃ as base and the reaction conditions are r.t. between 3 h and overnight.

For example XVI.8 DCM is used as solvent and the reaction conditions are0° C. for 1 h.

For the example XVI.17, XVI.19 and XVI.21 the reaction mixture isstirred at r.t. over night, diluted with water and extracted with EtOAc.The org. layers are combined, dried over MgSO₄, filtered and the solventis removed in vacuo.

For the example XVI.18/20 the reaction conditions are 4 h at 50° C. Thereaction is directly purified by HPLC.

HPLC Mass retention Starting spec time Ex. material Product structureresult (method) XVI.1 VII.1 + 2,4-dichloro pyrimidine

361 [M + H]⁺ 1.06 (G) XVI.2 X + 2,4-dichloro pyrimidine

419 [M + H]⁺ 0.96 (H) XVI.3 X + XIII.1

473 [M + H]⁺ 1.47 (E) XVI.4 XI + 2,4-dichloro- 5-fluoro pyrimidine

448 [M + H]⁺ 1.10 (F) XVI.5 VII.1 + 2,4-dichloro- 5-fluoro pyrimidine

379 [M + H]⁺ 0.95 (C) XVI.6 VII.1 + 4,5,6-trichloro- pyrimidine

395 [M + H]⁺ 1.24 (E) XVI.7 VII.1 + 2,4-dichloro pyrimidine

361 [M + H]⁺ 0.96 (I) XVI.8 VII.1 + 2,4-dichloro- 5-cyano pyrimidine

386 [M + H]⁺ 0.86 (B) XVI.9 VII.1 + 2,4,5-trichloro- pyrimidine

396 [M + H]⁺ 1.03 (C) XVI.10 VII.1 + 4,6-dichloro- 5-fluoro pyrimidine

379 [M + H]⁺ 0.97 (I) XVI.11 VII.1 + 2,4-dichloro- 5-methyl pyrimidine

375 [M + H]⁺ 0.93 (C) XVI.12 VII.1 + 2,4-dichloro- 5-bromo pyrimidine

439/441 [M + H]⁺ 1.04 (C) XVI.13 VII.1 + 4,6-dichloro- 5-methylpyrimidine

375 [M + H]⁺ 0.90 (I) XVI.14 VII.1 + 4,6-dichloro- pyrimidine

361 [M + H]⁺ 1.06 (G) XVI.15 XI + 2,4-dichloro- pyrimidine

430 [M + H]⁺ 0.90 (I) XVI.16 VII.1 + 4,6-dichloro- 5-methoxy pyrimidine

391 [M + H]⁺ 0.93 (D) XVI.17 X + 4,6-dichloro- 5-fluoro pyrimidine

437 [M + H]⁺ 1.39 (E) XVI.18 XI.2 + 4,5,6-trichloro- pyrimidine

550 [M + H]⁺ 1.09 (H) XVI.19 VII.1 + 2,4-dichloro-5- fluoro- pyrimidine

379 [M + H]⁺ 0.94 (I) XVI.20 IX.2 + 4,6-dichloro-5- methoxy- pyrimidine

546 [M + H]⁺ 0.83 (D) XVI.21 VII.1 + 2,4-dichloro-5- fluoro- pyrimidine

437 [M + H]⁺ 1.14 (I) XVI.22 IX.2 + 4,6-dichloro-5- fluoro- pyrimidine

534 [M + H]⁺ 0.89 (H)

Example XVII Example XVII.1 (General Route) tert-Butyl(S)-1-(4-((R)-1-(2-(ethyl(methyl)amino)pyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethylcarbamate

To 1.10 g (2.63 mmol) of product XVI.2 and 0.91 mL (5.25 mmol) DIPEA in20 mL EtOH are added 0.45 mL (5.25 mmol) N-ethylmethylamine and stirredat 80° C. for 4 d. Afterwards the reaction mixture is quenched by theaddition of water and extracted with DCM (2×). The combined org. layersare dried over MgSO₄, filtered and the solvent is removed in vacuo.

C₂₄H₃₅N₅O₃ (M=441.6 g/mol)

ESI-MS: 442 [M+H]⁺

R_(t) (HPLC): 1.19 min (method E)

The following compounds are prepared analogously to example XVII.1.

For example XVII.3 the reaction time is 5 h.

HPLC Mass retention Starting spec time Ex. material Structure result(method) XVII.1 XVI.2

442 [M + H]⁺ 1.19 (E) XVII.2 XVI.2

478 [M + H]⁺ 1.15 (E) XVII.3 XVI.2

470 [M + H]⁺ 0.94 (I)

Example XVIII Example XVIII.1 (General Route) tert-Butyl(S)-1-(4-((R)-1-(4-fluoro-6-(2-hydroxy-2-methylpropoxy)pyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethylcarbamate

80.0 mg (0.89 mmol) 2-methyl-propane-1,2-diol is added to 10 mL THF andcharged with 40.0 mg (0.92 mmol) NaH. After 10 min at r.t., 250 mg (0.57mmol) of example XVI.17 are added and the mixture is stirred at refluxover night. Then water and EtOAc are added and the layers are separated.The organic layer is washed with water (2×), dried over MgSO₄, filteredand the solvent is removed in vacuo. The residue is triturated withDIPE.

C₂₅H₃₅FN₄O₅ (M=490.6 g/mol)

ESI-MS: 491 [M+H]⁺

R_(t) (HPLC): 1.10 min (method I

The following compound is prepared analogously to example XVIII.1.

For example XVIII.2 dioxane is used as solvent and the reactionconditions are 2.5 h at 80° C.

HPLC Mass retention Starting spec time Ex. material Structure result(method) XVIII.2 XVI.17

497 [M + H]⁺ 1.21 (I)

Example XIX Example XIX.1 (General Route)1-(6-((R)-3-(4-((S)-1-Aminoethyl)phenoxy)pyrrolidin-1-yl)-5-fluoropyrimidin-4-yloxy)-2-methylpropan-2-olhydrochloride

To 130 mg (0.27 mmol) of example XVIII are added 10 mL of an ethanolicHCl solution (c=1.3 mol/L). The resulting mixture is stirred at r.t.over night. The solvent is removed in vacuo.

C₂₀H₂₇FN₄O₃*HCl (M=426.9 g/mol)

ESI-MS: 391 [M+H]⁺

R_(t) (HPLC): 0.82 min (method I)

The following compounds are prepared analogously to example XIX.1

For the examples XIX.2-XI5 the starting material is added to dioxane andcharged with an HCl solution in dioxane (c=4 mol/L). After removing ofthe solvent, the residue is triturated with TBME.

HPLC Mass retention Starting spec time Ex. material Product structureresult (method) XIX.1 XVIII

391 [M + H]+ 0.82 (I) XIX.2 XVII.1

342 [M + H]+ 0.90 (H) XIX.3 XVII.2

378 [M + H]+ 0.76 (E) XIX.4 XVII.3

370 [M + H]+ 1.02 (C) XIX.5 XXIV

398 [M + H]+ 0.78 (I) XIX.6 XXIV.2

388 [M + H]+ 0.70 (I) XIX.7 XVIII.2

380 [M + H]+ 0.92 (I)

Example XX Example XX.1 (General Route)(S)-1-(4-((R)-1-(6-(cyclopropylmethoxy)-5-fluoropyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethanamine

To 400 mg (0.85 mmol) of example XVI.3 in 10 mL DCM are added 25.6 mg(0.54 mmol) 2,6-lutidine and 254 mg (1.27 mmol) TMS-I and stirred atr.t. for 30 min. Then the reaction mixture is poured onto diluted aq.NaHCO₃ solution and extracted with DCM. The combined org. layers aredried over MgSO₄, filtered and the solvent is removed in vacuo.

C₂₀H₂₅FN₄O₂ (M=372.4 g/mol)

ESI-MS: 373 [M+H]⁺

R_(t) (HPLC): 0.95 min (method H)

The following compound is prepared analogously to example XX.1 Forexample XX.2 the reaction starts without 2,6-lutidine and the solvent isACN. The starting materials combined under icecooling. The reactionmixture is quenched with MeOH then extracted with NaHCO₃ solution andEE.

HPLC Mass retention Starting spec time Ex. material Product structureresult (method) XX.2 XXII.2

385 [M + H]+ 0.94 (I)

Example XXI(1S,3R)-3-amino-N—((S)-1-(4-((R)-1-(6-(cyclopropylmethoxy)-5-fluoropyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethyl)cyclopentanecarboxamide

a) 141 mg (0.62 mmol) (+)-(1S,3R)—N-BoC-3-aminocyclopentanecarboxylicacid, 32.3 μl (1.85 mmol) DIPEA and 198 mg (0.62 mmol) TBTU are added to5 mL DMF and stirred for 10 min. Then 230 mg (0.62 mmol) of the amine XXare added and the resulting mixture is stirred at r.t. over night.Afterwards the reaction is quenched by the addition of water and stirredat r.t. for 30 min. Then the precipitation is filtered, washed withwater and dried at 45° C.

C₃₁H₄₂FN₅O₅ (M=583.7 g/mol)

ESI-MS: 584 [M+H]⁺

R_(t) (HPLC): 1.20 min (method I)

b) To 200 mg (0.34 mmol) of the above mentioned product in 10 mL DCM areadded 39.7 μL (0.34 mmol) 2,6-lutidine and 73.5 μL (0.51 mmol) TMSI andstirred at r.t. for 30 min. Then the reaction mixture is poured into aq.NaHCO₃ solution and extracted with DCM. The combined org. layers aredried over MgSO₄, filtered and the solvent is removed in vacuo.

C₂₆H₃₄FN₅O₃ (M=483.6 g/mol)

ESI-MS: 484 [M+H]⁺

R_(t) (HPLC): 1.21 min (method E)

Example XXII Example XXII.1 (General Route)N—((S)-1-(4-((R)-1-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yloxy)phenyl)ethyl)acetamide

600 mg (2.11 mmol) of example VII.1, 275 mg (2.11 mmol)2-chloro-5-hydroxypyrimidine and 1.12 mL (6.53 mmol) DIPEA in 8 mL NMPare stirred at 150° C. for 6 h in a microwave oven. Afterwards thereaction mixture is directly purified by HPLC (MeOH/H₂O/NH₃).

C₁₈H₂₂N₄O₃ (M=342.4 g/mol)

ESI-MS: 343 [M+H]⁺

R_(t) (HPLC): 1.04 min (method J)

The following compound is prepared analogously to example XXII.1

HPLC Mass retention Starting spec time Ex. material Product structureresult (method) XXII.2 X + XIII.2

485 [M + H]+ 1.07 (H)

Example XXIII 4-Methyl-2-(propanoylamino)thiazole-5-carboxylic acid

13.4 g (84.7 mmol) of 2-amino-4-methyl-thiazole-5-carboxylic acid, 35.8ml (297 mmol) propionic acid anhydride in 90 ml propionic acid arestirred at 100° C. over night. The reaction is cooled to r.t. Then themixture is poured into water (200 ml). A precipitate is formed, filteredand washed with water. Then the filtrate is suspended in water andstirred for 30 min. The precipitate is filtered again and dried at 50°C. in an oven with recirculating air.

C₈H₁₀N₂O₃S (M=214.2 g/mol)

ESI-MS: 215 [M+H]⁺

R_(t) (HPLC): 0.68 min (method I)

Example XXIV Example XXIV.1 (General Route) tert-ButylN-[(1S)-1-[4-[(3R)-1-[2-(6-azaspiro[2.4]heptan-6-yl)-5-fluoro-pyrimidin-4-yl]pyrrolidin-3-yl]oxyphenyl]ethyl]carbamate

500 mg (1.14 mmol) of example XVI.21 and 330 mg (3.4 mmol)6-azaspiro[2.4]-heptane are dissolved in NMP. The reaction is heated at100° C. over night. The reaction is cooled to r.t. and diluted withwater. The precipitate is filtered off and dried at 40° C.

C₂₇H₃₆FN₅O₃ (M=497.60 g/mol)

ESI-MS: 498[M+H]⁺

R_(t) (HPLC): 1.04 min (method I)

The following compounds are prepared HPLC analogously to Mass retentionexample Starting spec time XXIV.1 Ex. material Product structure result(method) XXIV.2 XVI.21

488 [M + H]+ 0.70 (I)

Example XXV Ethyl 2-acetamido-4-methyl-oxazole-5-carboxylate

To 2 g (11.8 mmol) ethyl 2-amino-4-methyl-oxazole-5-carboxylate in 50 mlDCM are added 6.1 ml (35.3 mmol) DIPEA. To this mixture 0.92 ml (12.9mmol) acetyl chloride are added and the reaction mixture is stirred atr.t. for 2 h. The mixture is diluted with further DCM and washed withwater. The organic layer is separated, dried and the solvent is removedin vacuo.

C₉H₁₂N₂O₄ (M=212.08 g/mol)

The product was used without further characterization.

Example XXVI 2-Acetamido-4-methyl-oxazole-5-carboxylic acid

1.7 g (8.01 mmol) of Example XXV is dissolved in 10 ml ethanol. 5 ml of2N NaOH is added to the mixture and the reaction is stirred at r.t. overnight. The reaction is acidified with 2N HCl. EtOH is reduced in vacuo.The residue is stirred with 2-methoxy-2-methyl-propane. Then aprecipitate is formed which was filtered and dried at 40° C. in an ovenwith recirculating air. The product was used without furthercharacterization.

C₇H₈N₂O₄ (M=184.05 g/mol)

Example XXVII Ethyl 2-acetamido-oxazole-4-carboxylate

A mixture of 1 g (6.41 mmol) ethyl 2-aminooxazole-4-carboxylate and 9.1ml (96.3 mmol) acetic acid anhydride are stirred at r.t. over night. Thesolvent is removed in vacuo. Toluene is added and evaporated. Thisprocedure is repeated three times. C₈H₁₀N₂O₄ (M=198.06 g/mol)

ESI-MS: 199[M+H]⁺

Example XXVIII 2-Acetamido-oxazole-4-carboxylic acid

1.3 g (6.6 mmol) of Example XXVII are dissolved in 33 ml ethanol. 0.554g (13.2 mmol) lithium hydroxide monohydrate are added and the reactionis stirred at r.t. over night. The solvent was evaportated and theresidue is acidified with HCl. The resulting precipitate is filtrated,washed with cool water and dried.

C₆H₆N₂O₄ (M=170.03 g/mol)

ESI-MS: 171[M+H]⁺

Example XXIX 2-Chloro-5-(R)-2,2-difluorocyclopropylmethoxy)-pyrimidine

a) 33 g (0.27 mol) 2,2-Difluorocyclopropanecarboxylic acid are added to250 mL acetonitrile and charged with 40 mL (0.27 mol)(R)-1-(4-methoxyphenyl)ethylamine. After stirring at r.t. over night theprecipitate is filtered off and recrystallised (3×) with ACN. Theprecipitate is added to 150 mL DCM, charged with 100 mL aq. HCl solution(c=1 mol/L) and extracted. The aq. layer is extracted three times withDCM, the organic layers are combined, dried over Na₂SO₄, filtered andthe solvent is removed in vacuo.

C₄H₄F₂O₂ (M=122.1 g/mol)

ESI-MS: 121 [M−H]⁻

R_(t) (GC): 26.1 min (method a)

b) 7.2 g (59 mmol) R-2,2-difluoro-cyclopropanecarboxylic acid are addedto 100 mL THF, chilled to 0° C. and 35 mL (77 mmol) lithium aluminumhydride solution (2.2 M in 2-methyltetrahydrofuran) are added dropwise.The mixture is stirred at r.t. over night. After that the mixture ischilled to 0° C. and quenched by the addition of 3 ml water and 3 ml aq.NaOH solution (c=4 mol/L) slowly. The resulting mixture is stirred for30 min, filtered, washed with THF and the filtrate is concentrated byevaporation. The residue is added to Et₂O, dried over Na₂SO₄, filteredand the solvent is removed in vacuo.

C₄H₄F₂O (M=108.1 g/mol)

R_(t) (GC): 15.4 min (method a)

c) 2.16 g (20.0 mmol) of the above mentioned product, 2.75 g (20 mmol)1-chloro-5-hydroxypyrimidine and 6.56 g (25 mmol) triphenylphosphine areadded to 20 ml THF and cooled to 0° C. Then 11.5 mL (25 mmol)diethylazocarboxylate (40% in toluene) are added carefully at constanttemperature. Then cooling is removed and the mixture is stirred at r.t.for 3 h. Afterwards the solvent is removed in vacuo, diethylether isadded and the mixture is filtered. The solvent is removed in vacuo andthe residue is purified by flash chromatography (silica gel, PE/EtOAc)

C₈H₇ClF₂N₂O (M=220.60 g/mol)

ESI-MS: 221 [M+H]⁺

R_(t) (HPLC): 0.91 min (method I)

Preparation of Final Compounds Example 1 Example 1.1 (General Route)N—((S)-1-(4-((R)-1-(2-(cyclobutylamino)pyrimidin-5-yl)pyrrolidin-3-yloxy)phenyl)ethyl)acetamide

Method A)

To 60.0 mg (0.21 mmol) of the product VII.1 in 2 mL dioxane are added48.1 mg (0.21 mmol) 5-bromo-2-(cyclobutylamino)-pyrimidine, 83.5 mg(0.84 mmol) NaOtBu, 25.1 mg (0.08 mmol)2-(di-tert-butylphosphino)biphenyl and 19.3 mg (0.02 mmol) Pd₂(dba)₃.The mixture is degassed thoroughly and stirred at 45° C. over night. Tothe reaction mixture a small amount of water is added, the mixture isfiltered and afterwards directly purified by HPLC (MeOH/H₂O/NH₃).

Method B)

To 60.0 mg (0.21 mmol) of the product VII.1 in 2 mL dioxane are added48.1 mg (0.21 mmol) 5-bromo-2-(cyclobutylamino)-pyrimidine, 83.5 mg(0.84 mmol) NaOtBu and 31.0 mg (0.04 mmol)chloro(2-dicyclohexyl-phosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)(2-(2-aminoethyl)-phenyl)-palladium(II). The mixture is degassed thoroughly and stirred at 45° C. for 3 h.A small amount of water and MeOH are added, the mixture is filtered andafterwards purified by HPLC (MeOH/H₂O/TFA).

C₂₂H₂₉N₅O₂ (M=395.5 g/mol)

ESI-MS: 396 [M+H]⁺

R_(t) (HPLC): 1.00 min (method C)

The following compounds are prepared analogously to example 1.1.

For example 1.2 the reaction conditions are 80° C. for 1 h.

HPLC Mass retention Starting spec time Ex. material(s) Structure Methodresult (method) 1.1 VII.1 + 5- bromo-2- (cyclobutyl amino) pyrimidine

A 396 [M + H]⁺ 1.00 (C) 1.2 VII.1 + 5- bromo-2- (cyclo-butoxy)pyrimidine

A 397 [M + H]⁺ 1.06 (C) 1.3 VII.1 + 5- bromo-2- (cyclo-propyl methoxy)pyrimidine

B 397 [M + H]⁺ 1.22 (E) 1.4 XVI.18 + XII.3

B 587 [M + H]⁺ 0.96 (D)

Example 2 Example 2.1 (General Route)N—((S)-1-(4-((R)-1-(2-((2,2-difluoroethyl)(methyl)amino)pyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethyl)cyclopropanecarboxamide

14.6 mg (0.17 mmol) cyclopropanecarboxylic acid, 88.4 μl (0.51 mmol)DIPEA and 54.3 mg (0.17 mmol) TBTU are added to 3 mL DMF and stirred for10 min. Then 70.0 mg (0.17 mmol) of the amine XIX.3 are added and theresulting mixture is stirred at r.t. over night. Afterwards the mixtureis directly purified by HPLC (ACN/H₂O/TFA).

C₂₃H₂₉F₂N₅O₂ (M=445.5 g/mol)

ESI-MS: 446 [M+H]⁺

R_(t) (HPLC): 0.99 min (method E)

The following compounds are prepared analogously to example 2.1, usingthe appropriate carboxylic acid: For the examples 2.7, 2.15 and 2.17 theintermediate is added in methanol and the final product is treated withaq. HCl solution (c=1 mol/L) to cleave the THP protecting group.

For the examples where 1-chloro-N,N-2-trimethylpropenylamine is used,the reagent is added to the mixture of the appropriate acid in DCM andstirred at r.t. for 30 min.

For the examples 2.8-2.11, 2.13-2.14 and 2.16 the reaction time is 1 h.

For the examples 2.26-2.28 TEA is used as base.

For the examples 2.25-2.34 THF is used as solvent

HPLC Starting Mass retention material Coupling spec time Ex. (s) reagentStructure result (method) 2.1  XIX.3 TBTU

446 [M + H]⁺ 0.99 (E) 2.2  XIX.4 1-chloro- N,N-2- trimethyl- propenyl-amine

438 [M + H]⁺ 0.96 (E) 2.3  XIX.4 1-chloro- N,N-2- trimethyl- propenyl-amine

552 [M + H]⁺ 1.01 (E) 2.4  XIX.4 1-chloro- N,N-2- trimethyl- propenyl-amine

479 [M + H]⁺ 0.97 (E) 2.5  XIX.4 1-chloro- N,N-2- trimethyl- propenyl-amine

481 [M + H]⁺ 1.00 (E) 2.6  XIX.4 1-chloro- N,N-2- trimethyl- propenyl-amine

465 [M + H]⁺ 1.01 (C) 2.7  XIX.4 + XV TBTU

464 [M + H]⁺ 0.95 (H) 2.8  XIX.2 TBTU

524 [M + H]⁺ 1.07 (E) 2.9  XIX.2 TBTU

554 [M + H]⁺ 1.08 (E) 2.10 XIX.3 TBTU

560 [M + H]⁺ 1.03 (E) 2.11 XIX.3 TBTU

590 [M + H]⁺ 1.05 (E) 2.12 XIX.3 TBTU

487 [M + H]⁺ 1.02 (E) 2.13 XIX.2 TBTU

398 [M + H]⁺ 1.01 (E) 2.14 XIX.2 TBTU

410 [M + H]⁺ 1.03 (E) 2.15 XIX.3 TBTU

472 [M + H]⁺ 0.94 (E) 2.16 XIX.3 TBTU

434 [M + H]⁺ 0.97 (E) 2.17 XIX.2 TBTU

436 [M + H]⁺ 0.99 (E) 2.18 XIX.2 TBTU

451 [M + H]⁺ 1.05 (E) 2.19 XX  TBTU

555 [M + H]⁺ 1.08 (I) 2.20 XX  TBTU

467 [M + H]⁺ 1.01 (I) 2.21 XX  TBTU

468 [M + H]⁺ 1.06 (I) 2.22 XX  TBTU

482 [M + H]⁺ 0.90 (I) 2.23 XX  TBTU

429 [M + H]⁺ 1.08 (I) 2.24 XX  TBTU

582 [M + H]⁺ 1.20 (I) 2.25  XX.2 1-chloro- N,N-2- trimethyl- propenyl-amine

442 [M + H]⁺ 0.81 (W) 2.26  XX.2 1-chloro- N,N-2- trimethyl- propenyl-amine

568 [M + H]⁺ 0.52 (S) 2.27  XX.2 1-chloro- N,N-2- trimethyl- propenyl-amine

480 [M + H]⁺ 0.50 (S) 2.28  XX.2 1-chloro- N,N-2- trimethyl- propenyl-amine

497 [M + H]⁺ 0.68 (W) 2.29  XX.2 1-chloro- N,N-2- trimethyl- propenyl-amine

467 [M + H]⁺ 0.56 (S) 2.30  XX.2 1-chloro- N,N-2- trimethyl- propenyl-amine

485 [M + H]⁺ 0.91 (X) 2.31  XX.2 1-chloro- N,N-2- trimethyl- propenyl-amine

480 [M + H]⁺ 0.72 (Y) 2.32  XX.2 + XXVI 1-chloro- N,N-2- trimethyl-propenyl- amine

551 [M + H]⁺ 0.49 (S) 2.33  XX.2 + XXVIII 1-chloro- N,N-2- trimethyl-propenyl amine

537 [M + H]⁺ 0.48 (S)

Example 3 Example 3.1 (general route)3-((S)-1-(4-((R)-1-(2-((2,2-difluoroethyl)(methyl)amino)pyrimidin-4-yl)pyrrolidin-3-yloxy)phenylethyl)-1,1-dimethylurea

Method A)

To 0.17 mmol of the appropriate 1-phenethylamine and 0.42 mmol TEA in 3mL DCM are added to 0.19 mmol CDT and stirred for at r.t. 10 min. Then0.51 mmol of the other amine are added and the resulting mixture isstirred at r.t over night. Afterwards some DMF is added and the mixtureis directly purified by HPLC (ACN/H₂O/TFA).

C₂₂H₃₀F₂N₆O₂ (M=448.5 g/mol)

ESI-MS: 449 [M+H]⁺

R_(t) (HPLC): 0.97 min (method E)

Method B)

To 0.34 mmol of the appropriate heteroaniline in 3 mL dioxane are added0.34 mmol CDT and 0.34 mmol DBU and the resulting mixture is stirred atr.t. for 1 h. Then 0.17 mmol of the appropriate 1-phenethylamine areadded and stirring is continued over night. The mixture is purified byHPLC (ACN/H₂O/NH₃).

Method C)

To 0.17 mmol of the appropriate 1-phenethylamine in 2 mL THF and 0.43mmol DIPEA are added 0.20 mmol dimethylcarbamoyl chloride and theresulting mixture is stirred for 1 h at r.t. The mixture is filtered anddirectly purified by HPLC (ACN/H₂O/TFA).

Method D

The appropriate isocyante is used instead of the appropriate carbamoylchloride.

The following compounds are prepared analogously to example 3.1.

For the examples 3.3-3.5 and 3.7-3.9 the reaction conditions are 50° C.over night.

HPLC Mass retention Starting spec time Ex. material(s) Structure Methodresult (method) 3.1  XIX.3

A 449 [M + H]⁺ 0.97 (E) 3.2  XIX.4

A 441 [M + H]⁺ 1.00 (C) 3.3  XIX.4

A 441 [M + H]⁺ 0.79 (H) 3.4  XIX.4

A 453 [M + H]⁺ 0.80 (H) 3.5  XIX.4

B 480 [M + H]⁺ 0.83 (H) 3.6  XIX.4

A 483 [M + H]⁺ 0.79 (H) 3.7  XIX.4

A 455 [M + H]⁺ 0.84 (H) 3.8  XIX.4

A 427 [M + H]⁺ 0.76 (H) 3.9  XIX.2

A 413 [M + H]⁺ 1.02 (E) 3.10 XX 

A 444 [M + H]⁺ 1.08 (I) 3.11 XX 

A 430 [M + H]⁺ 1.03 (I) 3.12 XX 

A 486 [M + H]⁺ 1.06 (I) 3.13 XX 

B 483 [M + H]⁺ 1.11 (I) 3.14 XX 

A 444 [M + H]⁺ 1.06 (I) 3.15 XIX.1

C 462 [M + H]⁺ 0.51 (S) 3.16 XIX.5

C 469 [M + H]⁺ 0.43 (S) 3.17 XIX.5

D 469 [M + H]⁺ 0.43 (S) 3.18 XIX.6

C 459 [M + H]⁺ 0.71 (U) 3.19 XIX.7

C 468 [M + H]⁺ 0.55 (A.A) 3.20 XIX.6

D 459 [M + H]⁺ 0.36 (S)

Example 4 Example 4.1 (General Route) Methyl(S)-1-(4-((R)-1-(2-((2,2-difluoroethyl)(methyl)amino)pyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethylcarbamate

Method A)

70.0 mg (0.17 mmol) of the amine XIX.3 in 2 mL ACN are cooled to 5° C.in an ice-water bath. Then 71.2 μL (0.51 mmol) TEA and 19.6 μL (0.25mmol) methyl chloroformate are added and the resulting mixture isstirred at 5° C. for 2 h. The crude mixture is directly purified by HPLC(ACN/H₂O/TFA).

C₂₁H₂₇F₂N₅O₃ (M=435.5 g/mol)

ESI-MS: 436 [M+H]⁺

R_(t) (HPLC): 1.01 min (method E)

Method B)

To 70.0 mg (0.17 mmol) of amine XIX.3 in 2 mL DCM are added 30.7 mg(0.19 mmol) CDT and 21.2 μL (0.18 mmol) TEA and stirred at r.t. for 1 h.Then 10.3 μL (0.19 mmol) methanol is added and stirred at 35° C. overnight. The crude mixture is directly purified by HPLC (MeOH/H₂O/NH₃).

The following compounds are prepared analogously to example 4.1. Forexample 4.2 the reaction conditions are 50° C. over night.

For example 4.5 the reaction conditions are r.t. over night.

For example 4.6 the reaction is done in THF with DIPEA as base. Thereaction conditions are r.t. for 1 h.

HPLC Mass retention Starting spec time Ex. material Structure Methodresult (method) 4.1 XIX.3

A 436 [M + H]⁺ 1.01 (E) 4.2 XIX.4

B 428 [M + H]⁺ 1.05 (C) 4.3 XIX.4

A 442 [M + H]⁺ 0.89 (H) 4.4 XIX.2

A 400 [M + H]⁺ 1.04 (E) 4.5 XX 

A 431 [M + H]⁺ 1.13 (I) 4.6 XIX.1

A 449 [M + H]⁺ 0.53 (T)

Example 5 Example 5.1 (General Route)N—((S)-1-(4-((R)-1-(2-(ethyl(methyl)amino)pyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethyl)-2,2-difluoroacetamide

To 70.0 mg (0.19 mmol) of the amine XIX.2 and 96.8 μL (0.56 mmol) DIPEAin 3 mL THF are added 32.2 μL (0.19 mmol) difluoroacetic anhydride andthe mixture is stirred at r.t. over night. The mixture is directlypurified by HPLC (ACN/H₂O/TFA).

C₂₁H₂₇F₂N₅O₂ (M=419.5 g/mol)

ESI-MS: 420 [M+H]⁺

R_(t) (HPLC): 1.01 min (method E)

The following compounds are prepared analogously to example 5.1

HPLC Mass retention Starting spec time Ex. material Structure result(method) 5.1 XIX.2

420 [M + H]⁺ 1.01 (E) 5.2 XIX.3

456 [M + H]⁺ 0.96 (E) 5.3 XX 

451 [M + H]⁺ 1.11 (I)

Example 6 Example 6.1 (General Route)N—((S)-1-(4-((R)-1-(5-(cyclobutylmethoxy)pyrimidin-2-yl)pyrrolidin-3-yloxy)phenyl)ethyl)acetamide

80.0 mg (0.28 mmol) of the amine VII.1, 55.8 mg (0.28 mmol) of exampleXII.4 and 144 μL (0.84 mmol) DIPEA in 2 mL NMP are stirred at 100° C.for 30 min. The reaction mixture is directly purified by HPLC(ACN/H₂O/NH₃).

C₂₃H₃₀H₄O₃ (M=410.5 g/mol)

ESI-MS: 411 [M+H]⁺

R_(t) (HPLC): 0.93 min (method H)

The following compounds are prepared analogously to example 6.1.

For the examples 6.4-6.6 and 6.12-6.15 the reaction conditions are 35°C. over night.

For example 6.7 the reaction conditions are 150° C. over night.

For the examples 6.7-6.8 and 6.21 the reaction conditions are 120° C.for 1 h.

For the examples 6.9, 6.14-6.16 and 6.18 the reaction conditions are 70°C. over night.

For example 6.22 DMSO is used as solvent and the reaction conditions are60° C. over night.

HPLC Mass retention Starting spec time Ex. material Structure result(method) 6.1  VII.1 + XII.4

411 [M + H]⁺ 0.93 (H) 6.2  VII.4 + 2- chloro-5-ethyl- pyrimidine

355 [M + H]⁺ 1.86 (A) 6.3  VII.3 + 2- chloro-5-ethyl- pyrimidine

355 [M + H]⁺ 1.86 (A) 6.4  VII.3 + 2- chloro-5- cyclopropyl- pyrimidine

367 [M + H]⁺ 1.98 (A) 6.5  VII.3 + 2- chloro-5- propoxy- pyrimidine

385 [M + H]⁺ 2.03 (A) 6.6  VII.1 + 2- chloro-5-(iso- propoxy) Pyrimidine

385 [M + H]⁺ 0.83 (H) 6.7  VII.1 + 2- chloro-5- cyclopropyl- methoxypyrimidine

397 [M + H]⁺ 1.42 (J) 6.8  VII.1 + XII.3

433 [M + H]⁺ 1.19 (B) 6.9  VII.1 + 4- chloro-2- isopropyl- pyrimidine

369 M + H]⁺ 1.03 (C) 6.10 VII.1 + 2- chloro-4- (pyrrolidin-1-yl)pyrimidine

396 M + H]⁺ 1.11 (C) 6.11 VII.1 + 2- chloro-N- ethyl-N- methyl-4-pyrimidine

384 M + H]⁺ 1.08 (C) 6.12 VII.1 + 2- chloro-N- ethyl-5-fluoro-N-methyl-4- pyrimidine

402 M + H]⁺ 1.14 (C) 6.13 VII.1 + 2- chloro-N,N- diethyl-5- fluoro-4-pyrimidine

416 M + H]⁺ 1.19 (C) 6.14 XI + 4-(4- chloro- pyrimidin-2- yl)morpholine

481 M + H]⁺ 0.78 (D) 6.15 XI + XII.3

502 M + H]⁺ 0.97 (D) 6.16 XI + 4-chloro- 2-(trifluoro- methyl-pyrimidine

464 M + H]⁺ 1.01 (D) 6.17 XI + 2-chloro- 5-(cyclobutyl) pyrimidine

381 M + H]⁺ 0.88 (H) 6.18 XI + 2- chloro-5- (cyclopentyl) pyrimidine

395 M + H]⁺ 0.93 (H) 6.19 XI + XII.5

411 M + H]⁺ 0.91 (H) 6.20 XI + XII.1

399 M + H]⁺ 0.91 (H) 6.21 XI + 4-chloro- 2-(trifluoro- methyl)pyrimidine

395 M + H]⁺ 0.81 (H) 6.22 XI + 2-chloro- N-methyl-N- propyl- pyrimidine-4-amine

398 M + H]⁺ 1.17 (C) 6.23 VII.1 + 2- chloro-4- (trifluoro- methyl)pyrimidine

395 [M + H]⁺ 0.42 (K) 6.24 VII.1 + XIV

383 [M + H]⁺ 0.33 (K) 6.25 VII.1 + 2- chloro-5-n- propyl pyrimidine

369 [M + H]⁺ 0.32 (K) 6.26 VII.1 + XXIX

433 [M + H]⁺ 0.84 (H)

Example 7 Example 7.1 (General Route)N—((S)-1-(4-((R)-1-(6-(cyclopropylmethoxy)-5-fluoropyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethyl)acetamide

To 22.8 mg (0.32 mmol) cyclopropanemethanol in 2 mL THF are added 8.62mg (0.35 mmol) NaH and stirred at r.t. for 10 min. Then 60.0 mg (0.16mmol) of example XVI.10 are added and the resulting mixture is stirredat 80° C. over night. Afterwards the reaction mixture is filtered anddirectly purified by HPLC (MeOH/H₂O/NH₃).

C₂₂H₂₇FN₄O₃ (M=414.5 g/mol)

ESI-MS: 415 [m+H]⁺

R_(t) (HPLC): 1.14 min (method C)

The following compounds are prepared analogously to example 7.1.

For the examples 7.5-7.10 the reaction conditions are r.t. over night.

For example 7.13 DMSO is used as solvent and the reaction conditions are50° C. over night.

For the examples 7.14-7.18, 7.26-7.35, 7.37-7.42, 7.45-7.47, 7.52-7.53,7.57 the reaction conditions are 50° C. over night.

For the examples 7.20-7.25 DMSO is used as solvent and the reactionconditions are 80° C. for 1 h.

For the examples 7.45 and 7.48 example 7.5 is separated using chiralHPLC (column: Daicel Ciralpak® AYH (20×250 mm; 5 μm), 50% EtOH (with0.2% diethylamine) 50% CO₂, 150 bar, flow: 60 mL/min).

For the example 7.62, 7.66, 7.63 dioxane is used as solvent and thereaction conditions are 50° C. over night.

For the examples 7.65 dioxane is used as solvent and the reactionconditions are r.t. over night.

For the example 7.67 dioxane is used as solvent and the reactionconditions are 130° C. for 2 h

HPLC Mass retention Starting spec time Ex. material Structure result(method) 7.1  XVI.10

415 [M + H]⁺ 1.14 (C) 7.2  XVI.14

385 [M + H]⁺ 1.19 (G) 7.3  XVI.14

397 [M + H]⁺ 1.20 (G) 7.4  XVI.14

397 [M + H]⁺ 1.21 (G) 7.5  XVI.14

433 [M + H]⁺ 1.19 (G) 7.6  XVI.1 

397 [M + H]⁺ 1.19 (G) 7.7  XVI.1 

397 [M + H]⁺ 1.21 (G) 7.8  XVI.7 

385 [M + H]⁺ 1.30 (G) 7.9  XVI.14

425 [M + H]⁺ 1.23 (G) 7.10 XVI.7 

425 [M + H]⁺ 1.23 (G) 7.11 XVI.5 

415 [M + H]⁺ 1.26 (G) 7.12 XVI.5 

389 [M + H]⁺ 1.19 (G) 7.13 XXII + 2-fluoro- pyridine

420 [M + H]⁺ 1.41 (J) 7.14 XVI.5 

417 [M + H]⁺ 1.30 (G) 7.15 XVI.5 

425 [M + H]⁺ 1.16 (G) 7.16 XVI.5 

429 [M + H]⁺ 1.31 (G) 7.17 XVI.1 

399 [M + H]⁺ 1.24 (G) 7.18 XVI.5 

429 [M + H]⁺ 1.30 (G) 7.19 XVI.10

403 [M + H]⁺ 1.14 (C) 7.20 XVI.6 

431 [M + H]⁺ 1.11 (I) 7.21 XVI.6 

419 [M + H]⁺ 1.10 (I) 7.22 XVI.6 

405 [M + H]⁺ 1.05 (I) 7.23 XVI.13

399 [M + H]⁺ 0.91 (I) 7.24 XVI.13

385 [M + H]⁺ 0.86 (I) 7.25 XVI.13

411 [M + H]⁺ 0.92 (I) 7.26 XVI.10

389 [M + H]⁺ 0.85 (H) 7.27 XVI.10

415 [M + H]⁺ 0.93 (H) 7.28 XVI.10

417 [M + H]⁺ 0.96 (H) 7.29 XVI.10

440 [M + H]⁺ 0.82 (H) 7.30 XVI.10

425 [M + H]⁺ 0.85 (H) 7.31 XVI.10

421 [M + H]⁺ 0.85 (H) 7.32 XVI.10

433 [M + H]⁺ 0.78 (H) 7.33 XVI.10

439 [M + H]⁺ 0.89 (H) 7.34 XVI.10

451 [M + H]⁺ 0.90 (H) 7.35 XVI.10

409 [M + H]⁺ 0.90 (H) 7.36 XVI.10

471 [M + H]⁺ 0.72 (N) 7.37 XVI.10

445 [M + H]⁺ 0.82 (H) 7.38 XVI.10

431 [M + H]⁺ 0.82 (H) 7.39 XVI.6 

455 [M + H]⁺ 1.33 (E) 7.40 XVI.6 

467 [M + H]⁺ 1.33 (E) 7.41 XVI.6 

431 [M + H]⁺ 1.39 (E) 7.42 XVI.6 

449 [M + H]⁺ 1.23 (E) 7.43 XVI.10

464 [M + H]⁺ 1.06 (I) 7.44 XVI.16

401 [M + H]⁺ 0.89 (D) 7.45 XVI.10

451 [M + H]⁺ 5.60 (V) 7.46 XVI.10

447 [M + H]⁺ 0.57 (S) 7.47 XVI.10

429 [M + H]⁺ 0.64 (S) 7.48 XVI.10

451 [M + H]⁺ 3.48 (V) 7.49 XVI.16

451 [M + H]⁺ 0.99 (D) 7.50 XVI.16

415 [M + H]⁺ 0.92 (D) 7.51 XVI.16

415 [M + H]⁺ 0.94 (D) 7.52 XVI.6 

419 [M + H]⁺ 0.63 (S) 7.53 XVI.6 

445 [M + H]⁺ 0.69 (S) 7.54 XVI.16

437 [M + H]⁺ 0.95 (D) 7.55 XVI.16

441 [M + H]⁺ 0.98 (D) 7.56 XVI.16

463 [M + H]⁺ 0.97 (D) 7.57 XVI.6 

441 [M + H]⁺ 0.59 (S) 7.58 XVI.16

445 [M + H]⁺ 0.85 (D) 7.59 XVI.16

427 [M + H]⁺ 0.94 (D) 7.60 XVI.6 

463 [M + H]⁺ 0.62 (S) 7.61 XVI.16

459 [M + H]⁺ 0.93 (D) 7.62 XVI.18

586 [M + H]⁺ 1.01 (W) 7.63 XVI.20

581 [M + H]⁺ 0.85 (W) 7.64 XVI.6 

461 [M + H]⁺ 0.59 (S) 7.65 XVI.22

587 [M + H]⁺ 0.83 (H) 7.66 XVI.18

603 [M + H]⁺ 0.87 (H) 7.67 XVI.19

451 [M + H]⁺ 0.87 (I)

Example 8 Example 8.1 (General Route)N—((S)-1-(4-((R)-1-(2-(dimethylamino)-5-fluoropyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethyl)acetamide

80.0 mg (0.21 mmol) of example XVI.5 and 28.6 mg (0.63 mmol)dimethylamine are added to 1 mL NMP and stirred at 120° C. over night.Afterwards the reaction mixture is directly purified by HPLC(MeOH/H₂O/NH₃).

C₂₀H₂₆FN₅O₂ (M=387.5 g/mol)

ESI-MS: 388 [M+H]⁺

R_(t) (HPLC): 1.08 min (method C)

The following compounds are prepared analogously to example 8.1.

For the examples 8.2-8.13, 8.15, 8.22, 8.23, 8.27, 8.30-8.32, 8.36-8.46,8.57, 8.58, 8.61-8.62, 8.106-8.110 and 8.122-8.286, 8.291 DIPEA (3 eq)as base is added.

For the examples 8.14-8.25 the reaction conditions are 150° C. for 1 hin a microwave oven.

For the examples 8.33-8.35, 8.37-8.56, 8.60 and 8.62 the reactionconditions are 80° C. for 2 h.

For the examples 8.63-8.81, 8.83, 8.92-8.95, 8.308-8.311, 8.314 and8.316 EtOH is used as solvent, DIPEA (1.5 eq) as base and the reactionconditions are 80° C. over night.

For the examples 8.84-8.91, 8.97-8.101 and 8.302-8.304 DIPEA (3 eq) isused as base and the reaction conditions are 200° C. for 3 h in amicrowave oven.

For the examples 8.96 and 8.118-8.121 EtOH is used as solvent.

For the examples 8.102-8.105 and 8.111-8.117-Dioxan is used as solvent,DIPEA (3 eq) as base and the reaction conditions are 140° C. for 1 h ina microwave oven.

For the example 8.291 the product from the reaction (=example 8.269) wasseparated using chiral HPLC (Daicel Chiralpak® AS-H 20×250 mm, 5 μM, 60mL/min, T=40° C., 120 bar, 30% MeOH (with 0.2% diethylamine) and 70%CO₂) (Analytical detection with Daicel Chiralpak® AS-H, 250 mm×4.6 mm,5μ, 4 mL/min, 30% MeOH (with 0.2% diethylamine), 70% CO₂, R_(t)=2.29min, as earlier eluting diastereomer).

For the example 8.292-8.300 and 8.305-8.307, 8.312, 8.315, 8.317-8.319the reaction is done in dioxane at 100° C. in the presence of DIPEA asbase.

For the example 8.301 the reaction is done in dioxane at 140° C. in thepresence of DIPEA as base.

For the examples 8.320-8.321 sodium tert. butoxide is used as base, Thereaction is done in Dioxan and stirred at 50° C. over night.

HPLC Mass retention Starting spec time Ex. material Structure result(method) 8.1  XVI.5 

388 [M + H]⁺ 1.08 (C) 8.2  XVI.14

410 [M + H]⁺ 1.21 (G) 8.3  XVI.1 

410 [M + H]⁺ 1.29 (G) 8.4  XVI.1 

410 [M + H]⁺ 1.26 (G) 8.5  XVI.1 

396 [M + H]⁺ 1.24 (G) 8.6  XVI.1 

398 [M + H]⁺ 1.29 (G) 8.7  XVI.14

398 [M + H]⁺ 1.20 (G) 8.8  XVI.5 

428 [M + H]⁺ 1.35 (G) 8.9  XVI.5 

428 [M + H]⁺ 1.34 (G) 8.10  XVI.5 

428 [M + H]⁺ 1.31 (G) 8.11  XVI.5 

442 [M + H]⁺ 1.39 (G) 8.12  XVI.5 

414 [M + H]⁺ 1.30 (G) 8.13  XVI.5 

414 [M + H]⁺ 1.30 (G) 8.14  XVI.1 

370 [M + H]⁺ 0.80 (B) 8.15  XVI.1 

436 [M + H]⁺ 1.00 (B) 8.16  XVI.1 

410 [M + H]⁺ 0.90 (B) 8.17  XVI.1 

410 [M + H]⁺ 1.06 (B) 8.18  XVI.1 

410 [M + H]⁺ 1.00 (B) 8.19  XVI.1 

396 [M + H]⁺ 0.90 (B) 8.20  XVI.1 

424 [M + H]⁺ 1.00 (B) 8.21  XVI.1 

384 [M + H]⁺ 0.90 (B) 8.22  XVI.1 

460 [M + H]⁺ 1.00 (B) 8.23  XVI.1 

446 [M + H]⁺ 1.00 (B) 8.24  XVI.1 

398 [M + H]⁺ 0.90 (B) 8.25  XVI.1 

398 [M + H]⁺ 0.90 (B) 8.26  XVI.5 

416 [M + H]⁺ 1.19 (C) 8.27  XVI.5 

438 [M + H]⁺ 1.12 (C) 8.28 XVI.5 

446 M + H]⁺ 1.07 (C) 8.29  XVI.5 

458 M + H]⁺ 1.08 (C) 8.30  XVI.5 

456 M + H]⁺ 1.14 (C) 8.31  XVI.5 

402 M + H]⁺ 1.29 (G) 8.32  XVI.5 

460 M + H]⁺ 1.09 (C) 8.33  XVI.8 

449 M + H]⁺ 1.21 (C) 8.34  XVI.8 

423 M + H]⁺ 1.14 (C) 8.35  XVI.8 

423 M + H]⁺ 1.14 (C) 8.36  XVI.5 

442 M + H]⁺ 1.36 (G) 8.37  XVI.1 

409 [M + H]⁺ 0.93 (C) 8.38  XVI.1 

462 [M + H]⁺ 1.11 (C) 8.39  XVI.1 

462 [M + H]⁺ 1.12 (C) 8.40  XVI.1 

382 [M + H]⁺ 0.98 (C) 8.41  XVI.1 

440 [M + H]⁺ 1.02 (C) 8.42  XVI.1 

444 [M + H]⁺ 1.01 (C) 8.43  XVI.1 

432 [M + H]⁺ 1.07 (C) 8.44  XVI.1 

420 [M + H]⁺ 1.06 (C) 8.45  XVI.1 

418 [M + H]⁺ 1.07 (C) 8.46  XVI.1 

438 [M + H]⁺ 1.09 (C) 8.47  XVI.9 

432 [M + H]⁺ 1.24 (C) 8.48  XVI.11

412 [M + H]⁺ 0.76 (F) 8.49  XVI.1 

414 [M + H]⁺ 0.69 (F) 8.50  XVI.9 

430 [M + H]⁺ 0.74 (F) 8.51  XVI.9 

404 [M + H]⁺ 0.71 (F) 8.52  XVI.11

454 [M + H]⁺ 0.70 (F) 8.53  XVI.11

398 [M + H]⁺ 0.73 (F) 8.54  XVI.9 

474 [M + H]⁺ 0.71 (F) 8.55  XVI.9 

418 [M + H]⁺ 0.76 (F) 8.56  XVI.9 

418 [M + H]⁺ 0.73 (F) 8.57  XVI.12

462 [M + H]⁺ 1.20 (C) 8.58  XVI.12

448 [M + H]⁺ 1.15 (C) 8.59  XVI.12

474 [M + H]⁺ 1.21 (C) 8.60  XVI.9 

432 [M + H]⁺ 0.76 (F) 8.61  XVI.12

518 [M + H]⁺ 1.16 (C) 8.62  XVI.12

476 [M + H]⁺ 1.25 (C) 8.63  XVI.5 

416 [M + H]⁺ 0.95 (B) 8.64  XVI.5 

427 [M + H]⁺ 0.79 (B) 8.65  XVI.5 

394 [M + H]⁺ 0.85 (B) 8.66  XVI.5 

432 [M + H]⁺ 0.87 (B) 8.67  XVI.5 

436 [M + H]⁺ 0.91 (B) 8.68  XVI.5 

414 [M + H]⁺ 0.90 (B) 8.69  XVI.5 

450 [M + H]⁺ 0.92 (B) 8.70  XVI.5 

428 [M + H]⁺ 0.96 (B) 8.71  XVI.1 

412 [M + H]⁺ 0.77 (H) 8.72  XVI.1 

423 [M + H]⁺ 1.02 (C) 8.73  XVI.1 

410 [M + H]⁺ 1.17 (C) 8.74  XVI.1 

468 [M + H]⁺ 1.08 (C) 8.75  XVI.1 

422 [M + H]⁺ 1.20 (B) 8.76  XVI.1 

422 [M + H]⁺ 1.07 (C) 8.77  XVI.1 

421 [M + H]⁺ 0.82 (B) 8.78  XVI.1 

424 [M + H]⁺ 1.24 (C) 8.79  XVI.1 

452 [M + H]⁺ 0.97 (B) 8.80  XVI.7 

422 [M + H]⁺ 1.25 (B) 8.81  XVI.7 

424 [M + H]⁺ 1.27 (B) 8.82  XVI.5 

430 [M + H]⁺ 0.77 (D) 8.83  XVI.1 

464 [M + H]⁺ 1.23 (L) 8.84  XVI.1 

426 [M + H]⁺ 0.78 (D) 8.85  XVI.1 

440 [M + H]⁺ 0.81 (D) 8.86  XVI.1 

440 [M + H]⁺ 0.81 (D) 8.87  XVI.1 

440 [M + H]⁺ 0.80 (D) 8.88  XVI.1 

480 [M + H]⁺ 0.83 (D) 8.89  XVI.1 

440 [M + H]⁺ 0.80 (D) 8.90  XVI.1 

440 [M + H]⁺ 0.80 (D) 8.91  XVI.1 

428 [M + H]⁺ 0.80 (D) 8.92  XVI.10

428 [M + H]⁺ 1.17 (C) 8.93  XVI.10

388 [M + H]⁺ 1.03 (C) 8.94  XVI.10

402 [M + H]⁺ 1.01 (C) 8.95  XVI.10

416 [M + H]⁺ 1.16 (C) 8.96  XVI.9 

446 [M + H]⁺ 0.79 (D) 8.97  XVI.15

489 [M + H]⁺ 0.85 (I) 8.98  XVI.15

478 [M + H]⁺ 0.81 (I) 8.99  XVI.4 

457 [M + H]⁺ 0.81 (I) 8.100 XVI.13

412 [M + H]⁺ 0.85 (I) 8.101 XVI.13

398 [M + H]⁺ 0.83 (I) 8.102 XVI.6 

418 [M + H]⁺ 0.86 (I) 8.103 XVI.6 

430 [M + H]⁺ 0.86 (I) 8.104 XVI.6 

432 [M + H]⁺ 0.91 (I) 8.105 XVI.13

410 [M + H]⁺ 0.83 (I) 8.106 XVI.1 

428 [M + H]⁺ 0.84 (D) 8.107 XVI.1 

435 [M + H]⁺ 0.80 (D) 8.108 XVI.1 

463 [M + H]⁺ 0.86 (D) 8.109 XVI.1 

437 [M + H]⁺ 0.83 (D) 8.110 XVI.1 

479 [M + H]⁺ 0.83 (D) 8.111 XVI.6 

452 [M + H]⁺ 1.24 (E) 8.112 XVI.6 

444 [M + H]⁺ 1.23 (E) 8.113 XVI.6 

456 [M + H]⁺ 1.19 (E) 8.114 XVI.6 

466 [M + H]⁺ 1.25 (E) 8.115 XVI.6 

454 [M + H]⁺ 0.92 (H) 8.116 XVI.6 

457 [M + H]⁺ 0.86 (H) 8.117 XVI.6 

446 [M + H]⁺ 1.14 (E) 8.118 XVI.10

388 [M + H]⁺ 0.77 (H) 8.119 XVI.10

428 [M + H]⁺ 0.90 (H) 8.120 XVI.10

402 [M + H]⁺ 0.82 (H) 8.121 XVI.10

414 [M + H]⁺ 0.84 (H) 8.122 XVI.10

458 [M + H]⁺ 0.69 (D) 8.123 XVI.10

432 [M + H]⁺ 0.72 (H) 8.124 XVI.9 

458 [M + H]⁺ 0.81 (Q) 8.125 XVI.10

442 [M + H]⁺ 0.85 (Q) 8.126 XVI.9 

444 [M + H]⁺ 0.77 (Q) 8.127 XVI.9 

444 [M + H]⁺ 0.77 (Q) 8.128 XVI.9 

466 [M + H]⁺ 0.76 (Q) 8.129 XVI.10

414 [M + H]⁺ 0.72 (Q) 8.130 XVI.9 

448 [M + H]⁺ 0.70 (Q) 8.131 XVI.9 

443 [M + H]⁺ 0.68 (Q) 8.132 XVI.10

438 [M + H]⁺ 0.86 (Q) 8.133 XVI.10

414 [M + H]⁺ 0.72 (Q) 8.134 XVI.10

432 [M + H]⁺ 0.70 (Q) 8.135 XVI.10

416 [M + H]⁺ 0.77 (Q) 8.136 XVI.9 

454 [M + H]⁺ 0.74 (Q) 8.137 XVI.10

427 [M + H]⁺ 0.72 (Q) 8.138 XVI.10

428 [M + H]⁺ 0.81 (Q) 8.139 XVI.10

428 [M + H]⁺ 0.77 (Q) 8.140 XVI.10

450 [M + H]⁺ 0.86 (Q) 8.141 XVI.9 

432 [M + H]⁺ 0.75 (Q) 8.142 XVI.9 

444 [M + H]⁺ 0.78 (Q) 8.143 XVI.10

430 [M + H]⁺ 0.73 (Q) 8.144 XVI.10

416 [M + H]⁺ 0.78 (Q) 8.145 XVI.9 

430 [M + H]⁺ 0.73 (Q) 8.146 XVI.9 

458 [M + H]⁺ 0.75 (O) 8.147 XVI.10

442 [M + H]⁺ 0.74 (O) 8.148 XVI.10

458 [M + H]⁺ 0.80 (O) 8.149 XVI.9 

457 [M + H]⁺ 0.78 (O) 8.150 XVI.5 

446 [M + H]⁺ 0.77 (O) 8.151 XVI.9 

472 [M + H]⁺ 0.89 (O) 8.152 XVI.9 

458 [M + H]⁺ 0.86 (O) 8.153 XVI.9 

474 [M + H]⁺ 0.80 (O) 8.154 XVI.9 

444 [M + H]⁺ 0.84 (O) 8.155 XVI.5 

442 [M + H]⁺ 0.72 (O) 8.156 XVI.5 

444 [M + H]⁺ 0.73 (O) 8.157 XVI.5 

458 [M + H]⁺ 0.75 (O) 8.158 XVI.5 

470 [M + H]⁺ 0.82 (O) 8.159 XVI.10

470 [M + H]⁺ 0.95 O) 8.160 XVI.9 

460 [M + H]⁺ 0.78 O) 8.161 XVI.10

464 [M + H]⁺ 0.99 (O) 8.162 XVI.10

432 [M + H]⁺ 0.79 (O) 8.163 XVI.14

426 [M + H]⁺ 0.75 (O) 8.164 XVI.5 

430 [M + H]⁺ 0.84 (O) 8.165 XVI.5 

458 [M + H]⁺ 0.77 (O) 8.166 XVI.5 

458 [M + H]⁺ 0.76 (O) 8.167 XVI.5 

446 [M + H]⁺ 0.77 (O) 8.168 XVI.9 

462 [M + H]⁺ 0.79 (O) 8.169 XVI.9 

474 [M + H]⁺ 0.80 (O) 8.170 XVI.5 

444 [M + H]⁺ 0.75 (O) 8.171 XVI.1 

412 [M + H]⁺ 0.84 (O) 8.172 XVI.10

456 [M + H]⁺ 0.75 (O) 8.173 XVI.9 

474 [M + H]⁺ 0.80 (O) 8.174 XVI.9 

514 [M + H]⁺ 0.96 (O) 8.175 XVI.9 

483 [M + H]⁺ 0.81 (O) 8.176 XVI.10

458 [M + H]⁺ 0.86 (O) 8.177 XVI.10

446 [M + H]⁺ 0.81 (O) 8.178 XVI.9 

448 [M + H]⁺ 0.75 (O) 8.179 XVI.10

444 [M + H]⁺ 0.84 (O) 8.180 XVI.1 

440 [M + H]⁺ 0.76 (O) 8.181 XVI.5 

432 [M + H]⁺ 0.77 (O) 8.182 XVI.5 

458 [M + H]⁺ 0.79 (O) 8.183 XVI.5 

444 [M + H]⁺ 0.73 (O) 8.184 XVI.5 

432 [M + H]⁺ 0.77 (O) 8.185 XVI.9 

448 [M + H]⁺ 0.74 (O) 8.186 XVI.9 

460 [M + H]⁺ 0.79 (O) 8.187 XVI.9 

480 [M + H]⁺ 0.88 (O) 8.188 XVI.9 

474 [M + H]⁺ 0.82 (O) 8.189 XVI.9 

480 [M + H]⁺ 0.88 (O) 8.190 XVI.5 

428 [M + H]⁺ 0.82 (O) 8.191 XVI.9 

458 [M + H]⁺ 0.88 (O) 8.192 XVI.9 

490 [M + H]⁺ 0.87 (O) 8.193 XVI.5 

458 [M + H]⁺ 0.77 (O) 8.194 XVI.5 

442 [M + H]⁺ 0.86 (O) 8.195 XVI.1 

440 [M + H]⁺ 0.75 (O) 8.196 XVI.1 

394 [M + H]⁺ 0.77 (O) 8.197 XVI.10

458 [M + H]⁺ 0.82 (O) 8.198 XVI.10

498 [M + H]⁺ 1.09 (O) 8.199 XVI.10

442 [M + H]⁺ 0.88 (O) 8.200 XVI.10

414 [M + H]⁺ 0.81 (O) 8.201 XVI.10

444 [M + H]⁺ 0.77 (O) 8.202 XVI.10

444 [M + H]⁺ 0.71 (O) 8.203 XVI.1 

440 [M + H]⁺ 0.77 (O) 8.204 XVI.1 

428 [M + H]⁺ 0.77 (O) 8.205 XVI.5 

418 [M + H]⁺ 0.70 (O) 8.206 XVI.1 

452 [M + H]⁺ 0.82 (O) 8.207 XVI.1 

446 [M + H]⁺ 0.81 (O) 8.208 XVI.1 

446 [M + H]⁺ 0.80 (O) 8.209 XVI.9 

474 [M + H]⁺ 0.81 (O) 8.210 XVI.9 

460 [M + H]⁺ 0.78 (O) 8.211 XVI.9 

460 [M + H]⁺ 0.74 (O) 8.212 XVI.10

467 [M + H]⁺ 0.87 (O) 8.213 XVI.10

458 [M + H]⁺ 0.82 (O) 8.214 XVI.1 

426 [M + H]⁺ 0.72 (O) 8.215 XVI.5 

474 [M + H]⁺ 0.85 (O) 8.216 XVI.5 

444 [M + H]⁺ 0.74 (O) 8.217 XVI.5 

486 [M + H]⁺ 0.97 (O) 8.218 XVI.5 

464 [M + H]⁺ 0.82 (O) 8.219 XVI.9 

430 [M + H]⁺ 0.82 (O) 8.220 XVI.9 

460 [M + H]⁺ 0.76 (O) 8.221 XVI.9 

474 [M + H]⁺ 0.77 (O) 8.222 XVI.9 

502 [M + H]⁺ 1.14 (O) 8.223 XVI.9 

446 [M + H]⁺ 0.86 (O) 8.224 XVI.5 

458 [M + H]⁺ 0.78 (O) 8.225 XVI.9 

462 [M + H]⁺ 0.80 (O) 8.226 XVI.5 

440 [M + H]⁺ 0.84 (O) 8.227 XVI.1 

440 [M + H]⁺ 0.77 (O) 8.228 XVI.1 

440 [M + H]⁺ 0.79 (O) 8.229 XVI.1 

440 [M + H]⁺ 0.77 (O) 8.230 XVI.1 

414 [M + H]⁺ 0.77 (O) 8.231 XVI.10

486 [M + H]⁺ 1.19 (O) 8.232 XVI.10

428 [M + H]⁺ 0.88 (O) 8.233 XVI.10

428 [M + H]⁺ 0.83 (O) 8.234 XVI.10

444 [M + H]⁺ 0.77 (O) 8.235 XVI.10

440 [M + H]⁺ 0.86 (O) 8.236 XVI.10

458 [M + H]⁺ 0.81 (O) 8.237 XVI.10

430 [M + H]⁺ 0.72 (O) 8.238 XVI.5 

467 [M + H]⁺ 0.76 (O) 8.239 XVI.5 

432 [M + H]⁺ 0.72 (O) 8.240 XVI.5 

432 [M + H]⁺ 0.73 (O) 8.241 XVI.9 

448 [M + H]⁺ 0.79 (O) 8.242 XVI.1 

428 [M + H]⁺ 0.76 (O) 8.243 XVI.1 

424 [M + H]⁺ 0.85 (O) 8.244 XVI.5 

412 [M + H]⁺ 0.77 (O) 8.245 XVI.5 

430 [M + H]⁺ 0.71 (O) 8.246 XVI.1 

449 [M + H]⁺ 0.75 (O) 8.247 XVI.9 

486 [M + H]⁺ 0.85 (O) 8.248 XVI.9 

434 [M + H]⁺ 0.72 (O) 8.249 XVI.10

436 [M + H]⁺ 0.96 (O) 8.250 XVI.10

442 [M + H]⁺ 0.90 (O) 8.251 XVI.10

464 [M + H]⁺ 0.99 (O) 8.252 XVI.10

458 [M + H]⁺ 0.83 (O) 8.253 XVI.1 

410 [M + H]⁺ 0.83 (O) 8.254 XVI.5 

428 [M + H]⁺ 0.82 (O) 8.255 XVI.9 

474 [M + H]⁺ 0.78 (O) 8.256 XVI.9 

460 [M + H]⁺ 0.75 (O) 8.257 XVI.5 

498 [M + H]⁺ 0.86 (O) 8.258 XVI.9 

474 [M + H]⁺ 0.79 (O) 8.259 XVI.5 

444 [M + H]⁺ 0.76 (O) 8.260 XVI.1 

412 [M + H]⁺ 1.13 (P) 8.261 XVI.5 

464 [M + H]⁺ 0.82 (O) 8.262 XVI.5 

458 [M + H]⁺ 0.80 (O) 8.263 XVI.1 

414 [M + H]⁺ 0.72 (O) 8.264 XVI.1 

426 [M + H]⁺ 0.73 (O) 8.265 XVI.1 

414 [M + H]⁺ 0.76 (O) 8.266 XVI.9 

462 [M + H]⁺ 0.77 (O) 8.267 XVI.9 

444 [M + H]⁺ 0.84 (O) 8.268 XVI.10

430 [M + H]⁺ 0.90 (O) 8.269 XVI.10

444 [M + H]⁺ 0.72 (O) 8.270 XVI.10

446 [M + H]⁺ 0.79 (O) 8.271 XVI.5 

442 [M + H]⁺ 0.84 (O) 8.272 XVI.5 

456 [M + H]⁺ 0.74 (O) 8.273 XVI.5 

458 [M + H]⁺ 0.74 (O) 8.274 XVI.5 

444 [M + H]⁺ 0.76 (O) 8.275 XVI.5 

458 [M + H]⁺ 0.78 (O) 8.276 XVI.9 

456 [M + H]⁺ 0.86 (O) 8.277 XVI.1 

438 [M + H]⁺ 0.75 (O) 8.278 XVI.10

456 [M + H]⁺ 0.82 (O) 8.279 XVI.5 

456 [M + H]⁺ 0.75 (O) 8.280 XVI.9 

472 [M + H]⁺ 0.78 (O) 8.281 XVI.9 

444 [M + H]⁺ 0.98 (H) 8.282 XVI.5 

428 [M + H]⁺ 0.94 (H) 8.283 XVI.5 

428 [M + H]⁺ 0.94 (H) 8.284 XVI.10

428 [M + H]⁺ 0.91 (H) 8.285 XVI.9 

444 [M + H]⁺ 1.24 (P) 8.286 XVI.10

428 [M + H]⁺ 0.90 (H) 8.287 XVI.10

432 [M + H]⁺ 1.20 (R) 8.288 XVI.5 

444 [M + H]⁺ 1.12 (R) 8.289 XVI.9 

452 [M + H]⁺ 1.25 (R) 8.290 XVI.5 

458 [M + H]⁺ 1.19 (R) 8.291 XVI.10

444 [M + H]⁺ 0.72 (O) 8.292 XVI.10

444 [M + H]⁺ 0.36 (S) 8.293 XVI.10

428 [M + H]⁺ 0.91 (H) 8.294 XVI.10

428 [M + H]⁺ 0.91 (H) 8.295 XVI.16

456 [M + H]⁺ 0.55 (U) 8.296 XVI.6 

448 [M + H]⁺ 0.36 (S) 8.297 XVI.6 

460 [M + H]⁺ 0.37 (S) 8.298 XVI.6 

418 [M + H]⁺ 0.40 (S) 8.299 XVI.6 

460 [M + H]⁺ 0.38 (S) 8.300 XVI.16

456 [M + H]⁺ 0.36 (S) 8.301 XVI.16

414 [M + H]⁺ 0.71 (Q) 8.302 XVI.19

402 [M + H]⁺ 0.95 (I) 8.303 XVI.19

414 [M + H]⁺ 0.86 (I) 8.304 XVI.19

424 [M + H]⁺ 0.81 (I) 8.305 XVI.6 

446 [M + H]⁺ 0.75 (D) 8.306 XVI.22

569 [M + H]⁺ 0.67 (W) 8.307 XVI.18

584 [M + H]⁺ 0.71 (W) 8.308 XVI.6 

444 [M + H]⁺ 0.46 (S) 8.309 XVI.6 

430 [M + H]⁺ 0.43 (S) 8.310 XVI.6 

444 [M + H]⁺ 0.84 (U) 8.311 XVI.6 

444 [M + H]⁺ 0.67 (W) 8.312 XVI.18

572 [M + H]⁺ 0.69 (W) 8.313 XVI.6 

460 [M + H]⁺ 0.41 (S) 8.314 XVI.6 

432 [M + H]⁺ 0.45 (S) 8.315 XVI.18

594 [M + H]⁺ 0.76 (W) 8.316 XVI.6 

474 [M + H]⁺ 0.45 (S) 8.317 XVI.18

615 [M + H]⁺ 0.67 (W) 8.318 XVI.22

556 [M + H]⁺ 0.83 (X) 8.319 XVI.18

603 [M + H]⁺ 0.65 (W) 8.320 XVI.20

568 [M + H]⁺ 0.86 (H) 8.321 XVI.20

590 [M + H]⁺ 0.84 (D)

Example 9 Example 9.1 (General Route)N—((S)-1-(4-((R)-1-(2-(3-methoxyphenyl)pyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethyl)acetamide

To 70.0 mg (0.19 mmol) of the product XVI.1 in 4 mL toluene are added0.2 mL water, 5.93 mg (0.02 mmol) tricyclohexylphosphine, 144 mg (0.68mmol) K₃PO₄ and 88.4 mg (0.58 mmol) 3-methoxyphenylboronic acid and themixture is degassed thoroughly. Then 6.53 mg (0.03 mmol)palladium(II)acetate is added and the resulting mixture ist stirred at100° C. over night. Afterwards the reaction mixture is filtered. A smallamount of MeOH and DMF is added and the mixture is purified by HPLC(MeOH/H₂O/NH₃).

C₂₅H₂₈N₄O₃ (M=432.5 g/mol)

ESI-MS: 433 [M+H]⁺

R_(t) (HPLC): 0.97 min (method B)

The following compounds are prepared analogously to example 9.1. Forexample 9.2 the reaction is done in dioxane with PdCl₂(dppf) ascatalyst.

For the examples 9.3-9.4 the reaction is done in THF. The used catalystis PdCl₂(dppf) and the reaction conditions are 2.5 h at 60° C.

HPLC Mass retention Starting spec time Ex. material Structure result(method) 9.1 XVI.1

433 [M + H]⁺ 0.97 (B) 9.2 XVI.6 + cyclopropyl boronic acid

401 [M + H]⁺ 0.78 (Q) 9.3 XVI.10 + bromo(cyclo- butyl)zinc

399 [M + H]⁺ 0.89 H)  9.4 XVI.10 + bromo(cyclo- pentyl)zinc

413 [M + H]⁺ 0.93 (H) 9.5 XV I.10 + cyclopropyl- boronic acid

385 [M + H]⁺ 0.72 Z) 

Example 10 Example 10.1 (General Route)(1S,3R)-3-acetamido-N—((S)-1-(4-((R)-1-(6-(cyclopropylmethoxy)-5-fluoropyrimidin-4-yl)pyrrolidin-3-yloxy)phenyl)ethyl)cyclopentanecarboxamide

To 70.0 mg (0.15 mmol) of the amine XXI and 49.5 μL (0.29 mmol) DIPEA in2 mL DCM are added 11.4 mg (0.15 mmol) acetyl chloride and the mixtureis stirred at r.t. for 1 h. The resulting mixture is purified directlyby HPLC (ACN/H₂O/TFA).

C₂₈H₃₆FN₅O₄ (M=525.6 g/mol)

ESI-MS: 526 [M+H]⁺

R_(t) (HPLC): 1.34 min (method E)

The following compounds are prepared analogously to example 10.1.

For the examples 10.3-10.5 THF is used as solvent.

HPLC Mass retention Starting spec time Ex. materials Structure result(method) 10.1 XXI + acetyl chloride

526 [M + H]⁺ 1.34 (E) 10.2 XXI + methoxy- acetyl chloride

556 [M + H]⁺ 1.35 (E) 10.3 XX.2 + cyclopro- pane- carbonyl chloride

453 [M + H]⁺ 0.83 (W) 10.4 XIX.5 + cyclopro- pane- carbonyl chloride

 46 [M + H]⁺ 0.45 (S) 10.5 XIX.6 + cyclopro- pane- carbonyl

456 [M + H]⁺ 0.71 (U)

Analytic HPLC Methods Method A

Vol % water time (min) (incl. 0.2% NH₃) Vol % MeOH 0.00 95 5 0.20 95 52.20 5 95 2.30 5 95 2.40 0 100 2.60 0 100 Analytical column: XBridge C18(Waters); 2.5 μm; 3.0 × 30 mm; column temperature: 40° C.; flow: 1.3ml/min;

Method B

Vol % water time (min) (incl. 0.1% TFA) Vol % MeOH 0.00 95 5 0.05 95 51.40 0 100 1.80 0 100 Analytical column: Sunfire C18 (Waters) 2.5 μm;3.0 × 30 mm; column temperature: 60° C.; flow: 2.2 ml/min.

Method C

Vol % water time (min) (incl. 0.1% NH₃) Vol % MeOH 0.00 95 5 0.05 95 51.40 0 100 1.80 0 100 Analytical column: XBridge C18 (Waters) 2.5 μm;3.0 × 30 mm; column temperature: 60° C.; flow: 2.2 ml/min.

Method D

Vol % water time (min) (incl. 0.1% TFA) Vol % ACN Flow [ml/min] 0.00 973 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 3 1.40 0 100 3 Analyticalcolumn: Sunfire C18 (Waters) 2.5 μm; 3.0 × 30 mm; column temperature:60° C.

Method E

Vol % water time (min) (incl. 0.1% TFA) Vol % MeOH 0.00 95 5 0.05 95 51.40 0 100 1.80 0 100 Analytical column: Stablebond C18 (Waters) 1.8 μm;3.0 × 30 mm; column temperature: 60° C.; flow: 2.2 ml/min.

Method F

Vol % water time (min) (incl. 0.1% TFA) Vol % MeOH 0.00 95 5 0.15 95 51.70 100 0 2.25 100 0 Analytical column: Stablebond C18 (Waters) 3.5 μm;4.6 × 30 mm; column temperature: 60° C.; flow: 4.0 ml/min.

Method G

Vol % water Vol % Flow time (min) (incl. 0.1% NH₃) MeOH [ml/min] 0.00 955 2.2 0.30 95 5 2.2 1.50 0 100 2.2 1.55 0 100 2.9 1.70 0 100 2.9Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0 × 30 mm; columntemperature: 60° C.

Method H

Vol % water Flow time (min) (incl. 0.1% NH₃) Vol % ACN [ml/min] 0.00 973 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 3.0 1.40 0 100 3.0Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0 × 30 mm; columntemperature: 60° C.

Method I

Vol % water Flow time (min) (incl. 0.1% TFA) Vol % ACN [ml/min] 0.00 973 2.2 0.20 97 3 2.2 1.20 0 100 2.2 1.25 0 100 3.0 1.40 0 100 3.0Analytical column: Stablebond C18 (Agilent) 1.8 μm; 3.0 × 30 mm; columntemperature: 60° C.

Method J

Vol % MeOH Vol % water (incl. Flow time (min) (incl. 0.1% TFA) 0.1% TFA)[ml/min] 0.00 95 5 4.0 0.15 95 5 4.0 1.70 0 100 4.0 2.25 0 100 4.0Analytical column: Sunfire C18 (Waters) 3.5 μm; 4.6 × 30 mm; columntemperature: 60° C.

Method K

Vol % water Vol % ACN time (min) (incl. 0.1% TFA) (incl. 0.08% TFA) 0.0095.0 5.0 0.70 1.0 99.0 0.80 1.0 99.0 0.81 95.0 5.0 Analytical column:Ascentis Express C18; 2.7 μm; 2.1 × 50 mm; column temperature: 60° C.;flow: 1.5 ml/min;

Method L

Vol % water Flow time (min) (incl. 0.1% TFA) Vol % MeOH [ml/min] 0.00 955 1.9 0.20 95 5 1.9 1.55 0 100 1.9 1.60 0 100 2.4 1.80 0 100 2.4Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 × 30 mm; columntemperature: 60° C.

Method M

Vol % water Flow time (min) (incl. 0.1% TFA) Vol % MeOH [ml/min] 0.00 955 1.8 0.25 95 5 1.8 1.70 0 100 1.8 1.75 0 100 2.5 1.90 0 100 2.5Analytical column: Sunfire C18 (Waters) 2.5 μm; 3.0 × 30 mm; columntemperature: 60° C.

Method N

Vol % water Flow time (min) (incl. 0.1% TFA) Vol % ACN [ml/min] 0.00 5050 2.2 0.20 50 50 2.2 1.20 0 100 2.2 1.25 0 100 3.0 1.40 0 100 3.0Analytical column: Stablebond C18 (Agilent) 1.8 μm; 3.0 × 30 mm; columntemperature: 60° C.

Method O

Vol % water time (min) (incl. 0.1% TFA) Vol % ACN 0.00 98 2 1.50 0 1001.80 0 100 Analytical column: Sunfire C18 (Waters) 3.5 μm; 4.6 × 30 mm;column temperature: 60° C.; flow: 2.5 ml/min.

Method P

Vol % water time (min) (incl. 0.1% NH₃) Vol % ACN 0.00 98 2 1.50 0.0100.0 1.80 0.0 100.0 Analytical column: XBridge C18 (Waters) 3.5 μm; 4.6× 30 mm; column temperature: 60° C.; flow: 2.5 ml/min.

Method Q

Vol % water time (min) (incl. 0.1% TFA) Vol % ACN 0.00 98 2 1.50 0 1001.80 0 100 Analytical column: Sunfire C18 (Waters) 3.5 μm; 4.6 × 30 mm;column temperature: 60° C.; flow: 2.5 ml/min.

Method R

Vol % water Flow time (min) (incl. 0.1% TFA) Vol % ACN [ml/min] 0.00 973 4.0 0.15 97 3 3.0 2.15 0 100 3.0 2.20 0 100 4.5 2.40 0 100 4.5Analytical column: Sunfire C18 (Waters) 2.5 μm; 4.6 × 30 mm; columntemperature: 60° C.

Method S

Vol % water Vol % ACN time (min) (incl. 0.1% TFA) (incl. 0.08% TFA) 0.0095 5 0.75 0 100 0.85 0 100 Analytical column: Sunfire C18 (Waters) 2.5μm; 2.1 × 50 mm; column temperature: 60° C.; flow: 1.5 ml/min.

Method T

Vol % water Vol % ACN time (min) (incl. 0.1% NH₃) (incl. 0.08% TFA) 0.0095 5 0.80 0.1 99.9 0.90 0.1 99.9 Analytical column: XBridge C18 (Waters)1.7 μm; 3.0 × 30 mm; column temperature: 60° C.; flow: 1.5 ml/min.

Method U

Vol % water time (min) (incl. 0.1% NH₃) Vol % ACN 0.00 98.0 2 1.20 0 1001.40 0 100 Analytical column: XBridge C18 (Waters) 2.5 μm; 3.0 × 30 mm;column temperature: 60° C.; flow: 2.0 ml/min.

Method V

Vol % EtOH time (min) Vol % CO₂ (incl. 0.2% diethylamine) 0.00 50 5010.00 50 50 Analytical column: Daicel Chiralpak ® AYH, 5 μm; 4.6 × 250mm, flow: 4.0 ml/min.

Method W

Vol % water time (min) (H2O 0.1% TFA) Vol % ACN 0.00 98.0 2 1.20 0 1001.40 0 100 Analytical column: Sunfire C18_3.0 × 30 mm, 2.5 μm; columntemperature: 60° C.; flow: 2.0 ml/min.

Method X

Vol % water time (min) (H2O 0.1% NH4OH]) Vol % ACN 0.00 98.0 2 1.20 0100 1.40 0 100 Analytical column: XBridge C18_3.0 × 30 mm, 2.5 μm columntemperature: 60° C.; flow: 2.0 ml/min.

Method Y

Vol % water time (min) (H2O 0.1% TFA]) Vol % ACN 0.0 99.0 1 0.9 0 1001.1 0 100 Analytical column: Sunfire C18_3.0 × 30 mm, 2.5 μm columntemperature: 60° C.; flow: 2.0 ml/min.

Method Z

Vol % water time (min) (H2O 0.1% TFA]) Vol % ACN 0.00 98.0 2 1.50 0 1001.80 0 100 Analytical column: SunFire C18_4.6 × 30 mm, 3.5 μm columntemperature: 60° C.; flow: 2.5 ml/min.

Method AA

Vol % water time (min) (H2O 0.1% NH4OH) Vol % ACN 0.0 95.0 5.0 0.75 0.199.9 0.8 0.1 99.9 0.81 95.0 5.0 1.1 95.0 5.0 Analytical column: TriartC18_2.0 × 30 mm, 1.9 μm column temperature: 60° C.; flow: 1.5 ml/min.

Analytic GC Method Method a

Type: GC 7890

Carrier gas: helium

Column: BGB-175; 50 m; 0.25 mm ID; 0.25 μm DF (30 m and 20 m columncoupled)

Injector temperature: 220° C.

Flow: 5.0 ml/Min

Temperature program: 50° C., 0 min; 3° C./min to 160° C. 00 min hold

1. A compound of formula I

wherein Ar is selected from the group consisting of phenylene andpyridinylene, which are each optionally substituted with one or twosubstituents independently selected from the group consisting of F, Cl,—O—CH₃ and CH₃; R¹ independently of one another are selected from thegroup consisting of halogen, CN, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl,—O—(C₁₋₆-alkyl), —S—(C₁₋₃-alkyl), —O—(C₃₋₆-cycloalkyl),—O—(C₆₋₆-cycloalkenyl), —O—(CH₂)₁₋₂—(C₃₋₆-cycloalkyl),—O—(C₁₋₃-alkyl)-aryl, —O—CH₂—(C₂₋₄-alkenyl), —O—CH₂—(C₂₋₄-alkinyl),—O—CH₂-heterocyclyl, —O—CH₂-heteroaryl, —O-heterocyclyl, —O-aryl,—O-heteroaryl, —(C═O)—NH-aryl, —NR^(N1)R^(N2),

wherein R^(N1) is H, —CD₃, or C₁₋₃-alkyl, and R^(N2) is H, —CD₃,C₁₋₆-alkyl, C₃₋₆-cycloalkyl, —(CH₂)₁₋₂—(C₃₋₆-cycloalkyl), heterocyclyl,—CH₂-heterocyclyl, or aryl, or wherein R^(N1) and R^(N2) are connectedand together with the N-atom to which they are attached form anazetidinyl, pyrrolidinyl, piperidinyl, 2,5-dihydro-1H-pyrrolyl,morpholinyl, thiomorpholinyl, or [1,4]oxazepanyl ring, wherein each ofsaid rings is optionally substituted with one to four F, or one or twoCN, OH, C₁₋₃-alkyl, —O—C₁₋₃-alkyl or —(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl), saidsubstituents being the same or different, wherein heterocyclyl istetrahydrofuranyl or tetrahydropyranyl, wherein heteroaryl is selectedfrom the group consisting of pyridinyl, pyrimidinyl, pyridazinyl andpyrazinyl, wherein aryl is selected from the group consisting of phenyl,indanyl and naphthyl, wherein each alkyl is linear or branched and isoptionally substituted with 1 to 6 F or with one or two CN, —OH,—O—(C₁₋₄-alkyl) or phenyl, wherein each cycloalkyl is optionallysubstituted with 1 to 4 F or with one CN, OH, CH₃, CF₃ or—SO₂—(C₁₋₃-alkyl), and wherein each aryl or heteroaryl is optionallysubstituted with one or two substituents independently selected from thegroup consisting of F, Cl, C₁₋₃-alkyl and —O—(C₁₋₃-alkyl); n is 1, 2 or3; R² is H, F, Cl, CN or —O—(C₁₋₃-alkyl); R³ is H or C₁₋₃-alkyl; L isstraight-chain C₁₋₃-alkylene, which is optionally substituted with oneor two C₁₋₃-alkyl groups; and T is selected from the group consistingof: H, linear or branched C₁₋₆-alkyl which is optionally substitutedwith one to six F, with one CN, OH, —O—CH₃ or —O—C(═O)—CH₃, or with aheteroaryl group selected from the group consisting of oxazolyl,thiazolyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidinyland pyrazinyl, wherein each of said heteroaryl groups is optionallysubstituted with one or two substituents, which are independently ofeach other selected from the group consisting of C₁₋₃-alkyl,—(C₁₋₃-alkyl)-O—CH₃ and —NH—(C═O)—(C₁₋₃-alkyl); C₃₋₆-cycloalkyl which isoptionally substituted with one or two F, CN, C₁₋₃-alkyl, CF₃, OH,—O—(C₁₋₃-alkyl), —NH₂, —NH—(C═O)—(C₁₋₃-alkyl),—NH—(C═O)—(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl), —NH—(C═O)—O—(C₁₋₆-alkyl),—C(═O)—NH₂, —C(═O)—NH(C₁₋₃-alkyl) or —C(═O)—N(C₁₋₃-alkyl)₂, wherein thesubstituents are identical or different; —O—(C₁₋₄-alkyl) which isoptionally substituted with C₃₋₇-cycloalkyl; —NR⁴R⁵, wherein R⁴ is H orC₁₋₃-alkyl, and R⁵ is H, C₁₋₃-alkyl, —(C₁₋₃-alkyl)-β-CH₃ or a 5-memberedheteroaryl group containing 1 to 3 heteroatoms selected independentlyfrom O, S, N and NH, wherein said heteroaryl group is optionallysubstituted with C₁₋₃-alkyl; or wherein R⁴ and R⁵ are connected andtogether with the N to which they are attached form an azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring that isoptionally substituted with one or two C₁₋₃-alkyl or with one—NH—(C═O)—CH₃; and a 5-membered heteroaryl group containing one to threeheteroatoms selected independently from O, S, N and NH, which isoptionally substituted with one or two substituents selectedindependently from the group consisting of C₁₋₃-alkyl, —NH₂,—NH—C(═O)—C₁₋₃-alkyl, —NH—C(═O)—(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl),—NH—C(═O)—(C₁₋₃-alkyl)-OH, —NH—C(═O)—O—(C₁₋₆-alkyl) and —O—(C₁₋₂-alkyl),wherein each alkyl group is optionally substituted with one to three For with one OH; or a tautomer or salt thereof.
 2. A compound accordingto claim 1, wherein Ar is

wherein the before mentioned group is optionally monosubstituted with F;R² is H, F or —O—CH₃; and R³ is H.
 3. A compound according to claim 2,wherein Ar is

L is —CH(CH₃)—; and R² is H.
 4. A compound according to claim 1, whereinR¹ is selected from the group consisting of: F, Cl, Br, CN, C₁₋₄-alkyl,C₃₋₆-cycloalkyl, phenyl, —O—(C₁₋₅-alkyl), —O—(C₃₋₆-cycloalkyl),—O—(C₅₋₆-cycloalkenyl), —O—(CH₂)₁₋₂—(C₃₋₆-cycloalkyl),—O—(C₁₋₂-alkyl)-phenyl, —CH₂—(C₂₋₄-alkenyl), —O—CH₂-heterocyclyl,—O—CH₂-pyridinyl, —O-heterocyclyl, —O-phenyl, —O-pyridinyl,—NR^(N1)R^(N2),

wherein R^(N1) is H, —CD₃, or C₁₋₃-alkyl, and R^(N2) is —CD₃,C₁₋₅-alkyl, C₃₋₆-cycloalkyl, —CH₂—(C₃₋₆-cycloalkyl), heterocyclyl,—CH₂-heterocyclyl or phenyl, or wherein R^(N1) and R^(N2) are connectedand together with the N-atom to which they are attached form anazetidinyl, pyrrolidinyl, piperidinyl, 2,5-dihydro-1H-pyrrolyl,morpholinyl, thiomorpholinyl or [1,4]oxazepanyl ring, wherein each ofsaid rings is optionally substituted with one to four F or with one ortwo CN, OH, C₁₋₃-alkyl, —O—C₁₋₃-alkyl, or —C₁₋₃-alkyl-O—C₁₋₃-alkyl, saidsubstituents being the same or different, wherein heterocyclyl istetrahydrofuranyl or tetrahydropyranyl, wherein each alkyl is linear orbranched and is optionally substituted with 1 to 6 F or with one or twoCN, —OH, —O—(C₁₋₄-alkyl) or phenyl, wherein each cycloalkyl isoptionally substituted with 1 to 4 F or with one CN, OH, CH₃ or—SO₂—CH₃, and wherein each phenyl is optionally substituted with one F,Cl or —O—(C₁₋₃-alkyl).
 5. A compound according to claim 1, wherein R¹ isselected from the group consisting of: F, Cl, CN, C₁₋₄-alkyl,C₃₋₅-cycloalkyl, phenyl, —O—(C₁₋₅-alkyl), —O—(C₃₋₆-cycloalkyl),—O-tetrahydrofuranyl, —O—CH₂—(C₃₋₄-cycloalkyl), —NR^(N1)R^(N2) and

wherein R^(N1) is H, —CD₃, or C₁₋₂-alkyl, and R^(N2) is —CD₃,C₁₋₄-alkyl, C₃₋₆-cycloalkyl, or —CH₂—(C₃₋₆-cycloalkyl), or whereinR^(N1) and R^(N2) are connected and together with the N-atom to whichthey are attached form an azetidinyl, pyrrolidinyl, piperidinyl ormorpholin ring, wherein each of said rings is optionally substitutedwith one or two F, OH or CH₃, said substituents being the same ordifferent, wherein each alkyl is linear or branched and is optionallysubstituted with 1 to 3 F or with one —O—CH₃ or OH; wherein eachC₃₋₆-cycloalkyl is optionally substituted with 1 to 2 F or with one CN,OH or CH₃; and wherein each phenyl is optionally substituted with one—O—CH₃.
 6. A compound according to claim 1, wherein T is selected fromthe group consisting of: H, linear or branched C₁₋₄-alkyl which isoptionally substituted with one to six F, or with one CN, —O—CH₃ or OHor with a heteroaryl group selected from the group consisting ofoxazolyl, thiazolyl, pyrrolyl, isoxazolyl, pyrimidinyl and pyrazinyl,wherein each of said heteroaryl groups is optionally substituted withone or two substituents, which are independently of each other selectedfrom the group consisting of C₁₋₃-alkyl, —(C₁₋₃-alkyl)-O—CH₃ and—NH—(C═O)—(C₁₋₃-alkyl); C₃₋₆-cycloalkyl which is optionally substitutedwith one or two F, CN, C₁₋₃-alkyl, CF₃, —NH—(C═O)—(C₁₋₃-alkyl),—NH—(C═O)—(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl) or —NH—(C═O)—O—(C₁₋₄-alkyl),wherein the substituents are identical or different; —O—(C₁₋₃-alkyl)which is optionally substituted with one C₃₋₅-cycloalkyl; —NR⁴R⁵,wherein R⁴ is H or C₁₋₃-alkyl, and R⁵ is H, C₁₋₃-alkyl,—(C₁₋₃-alkyl)-O—CH₃ or a 5-membered heteroaryl group containing 1 to 3heteroatoms selected independently from O, S, N and NH, which isselected from the group consisting of oxazolyl, thiazolyl, pyrrolyl,isoxazolyl, isothiazolyl and imidazolyl; or wherein R⁴ and R⁵ areconnected and together with the N to which they are attached form anazetidinyl, pyrrolidinyl, piperidinyl or morpholinyl ring that isoptionally substituted with one or two C₁₋₃-alkyl or with one—NH—(C═O)—CH₃; and a 5-membered heteroaryl group containing one to threeheteroatoms selected independently from O, S, N and NH, which isoptionally substituted with one or two substituents selectedindependently from the group consisting of C₁₋₃-alkyl, —O—(C₁₋₂-alkyl),—NH—C(═O)—C₁₋₃-alkyl and —NH—C(═O)—(C₁₋₃-alkyl)-O—CH₃.
 7. A compoundaccording to claim 1, wherein T is selected from the group consistingof: linear or branched C₁₋₃-alkyl which is optionally substituted withone to six F, or with one CN, OH or —O—CH₃, or with a heteroaryl groupselected from the group consisting of thiazolyl, isoxazolyl andpyrimidinyl, wherein each of said heteroaryl groups is optionallysubstituted with one or two substituents, which are independently ofeach other selected from the group consisting of C₁₋₃-alkyl,—(C₁₋₃-alkyl)-O—CH₃ and —NH—(C═O)—CH₃; C₃₋₆-cycloalkyl which isoptionally substituted with one or two F or one CN, CF₃, C₁₋₃-alkyl,—NH—(C═O)—(C₁₋₃-alkyl), —NH—(C═O)—(C₁₋₃-alkyl)-O—(C₁₋₃-alkyl) or—NH—(C═O)—O—(C₁₋₄-alkyl); —O—(C₁₋₃-alkyl) which is optionallysubstituted with one cyclopropyl; —NR⁴R⁵, wherein R⁴ is H or C₁₋₃-alkyl,and R⁵ is H, C₁₋₃-alkyl, —(C₁₋₃-alkyl)-O—CH₃ or isoxazolyl; or whereinR⁴ and R⁵ are connected and together with the N to which they areattached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinylring that is optionally substituted with one or two C₁₋₃-alkyl or withone —NH—(C═O)—CH₃; and a furanyl, thiazolyl, oxazolyl, pyrazolyl,isoxazolyl, isothiazolyl or thiadiazolyl group, each of which isoptionally substituted with one or two substituents selectedindependently from the group consisting of C₁₋₃-alkyl,—NH—C(═O)—(C₁₋₃-alkyl)-O—CH₃ and —NH—C(═O)—C₁₋₃-alkyl.
 8. A compoundaccording to claim 1 having the formula

wherein n is 1 or 2 or 3; R¹ is selected from the group consisting ofC₁₋₄-alkyl, —O—(C₁₋₅-alkyl), —O—(C₃₋₆-cycloalkyl), —O-pyridinyl,—NR^(N1)R^(N2),

wherein R^(N1) is H or C₁₋₂-alkyl, and R^(N2) is C₁₋₅-alkyl orC₃₋₆-cycloalkyl, wherein each alkyl is linear or branched and isoptionally substituted with 1 to 3 F or with one or two CN, OH,—O—(C₁₋₃-alkyl) or phenyl; or, if n is 2, the second R¹ group isselected from the group consisting of F, Cl, Br, CN, CH₃ and —O—CH₃; R²is H; and T is selected from a group consisting of: linear or branchedC₁₋₃-alkyl which is optionally substituted with one to three F,C₃₋₆-cycloalkyl which is optionally substituted with one F, CH₃,—NH—(C═O)—CH₃, —NH—(C═O)—CH₂—O—CH₃ or —NH—(C═O)—O—(C₁₋₄-alkyl);—O—(C₁₋₂-alkyl) which is optionally substituted with one cyclopropyl;—NR⁴R⁵, wherein R⁴ is H or C₁₋₃-alkyl, and R⁵ is C₁₋₃-alkyl orisoxazolyl; or wherein R⁴ and R⁵ are connected and together with the Nto which they are attached form an azetidinyl, pyrrolidinyl, piperidinylor morpholinyl ring; and a furanyl, thiazolyl, oxazolyl, pyrazolyl,isoxazolyl or isothiazolyl group, each of which is optionallysubstituted with one or two substituents selected independently from thegroup consisting of CH₃, —NH—C(═O)—CH₂—O—CH₃, —NH—C(═O)—CH₃ and—NH—C(═O)—CH₂CH₃; or a salt thereof.
 9. A compound according to claim 1having the formula

wherein n is 1 or 2; R¹ is selected from a group consisting of:—O—(C₁₋₅-alkyl), which is optionally substituted with 1-3 F or one OH;—O—CH₂—(C₃₋₅-cycloalkyl), which is optionally substituted with 1-2 F;—O—(C₃₋₆-cycloalkyl); —NR^(N1)R^(N2), wherein R^(N1) is H, —CD₃ orC₁₋₂-alkyl; and R^(N2) is C₁₋₄-alkyl or C₃₋₆-cycloalkyl, wherein eachalkyl is optionally substituted with 1 to 3 F or with one OH or —O—CH₃;

or, if n is 2, the second R¹ group is selected from the group consistingof F, Cl, Br, CN, CH₃ and —O—CH₃; R² is H; and T is selected from thegroup consisting of: —CH₃, —CHF₂, —CH₂CH₃, —N(CH₃)₂, —OCH₃,

or a pharmaceutically acceptable salt thereof.
 10. A compound accordingto claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticallyacceptable salt of a compound according to any of claims 1 to
 8. 12. Amethod of treating obesity or type 2 diabetes which comprisesadministering, to a host suffering from obesity or type-2 diabetes, atherapeutically effective amount of a compound according to claim
 1. 13.A pharmaceutical composition comprising a compound according to claim 1,together with a pharmaceutically acceptable carrier or diluent.